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Sample records for acute myeloid leukemia

  1. Acute Myeloid Leukemia in Childhood

    OpenAIRE

    Yöntem, Ahmet; Bayram, İbrahim

    2018-01-01

    Acute leukemia is basically divided intoacute lymphoblastic leukemia and acute myeloid leukemia. About 15-20% ofchildhood leukemia is caused by acute myeloid leukemia.AML is classified according to morphological, cytochemical and immunophenotypiccharacteristics. AML patients may present with various clinical signsand symptoms due to leukemic cell infiltration. Age, gender, race, structuralfeatures of the patient and cytogenetic abnormalities are important factorsaffecting prognosis in AML. Th...

  2. [Acute myeloid Leukemia].

    Science.gov (United States)

    Braess, Jan

    2016-11-01

    Acute myeloid leukemia (AML) has been genetically characterized extensively and can now be subdivided into 9 to 11 pathogenetically different subtypes according to their profile of driver mutations. In clinical practice karyotyping and molecular analysis of NPM1, cEBPa and FLT3-ITD are required for treatment stratification and potentially genotype specific treatment. Some markers such as NPM1 not only offer prognostic information but can also serve as markers of minimal residual disease and thus have the potential to guide therapy in the future.The basis of curative treatment is intensive combination chemotherapy comprizing cytarabine and an anthracycline ("7 + 3" regimen). The prolonged duration of aplasia can be reduced significantly by accelerated therapy ("S-HAM" regimen). Following achievement of a complete remission patients with a low risk of relapse - based on genetic and clinical features - receive chemotherapy based consolidation therapy whereas high risk patients - and potentially also those with an intermediate risk - receive an allogeneic stem cell transplantation. Whereas adding the rather unspecific tyrosinekinase inhibitor sorafenib to standard treatment in unselected AML patients has not improved overall survival (OS), the addition of midostaurin to standard therapy in the selected group FLT3 mutated patients has resulted in a moderate but significant OS benefit.Real world data show that in patients below 50 years a cure rate of ca. 50 % can be achieved. However less than 10 % of patients above the age of 70 will be alive after five years even after intensive treatment. Therefore when curative and intensive treatment is deemed impossible the therapeutic standard in elderly and unfit patients used to be low-dose cytarabine with an average OS of 4 months. This has now been replaced by a new standard of care of hypomethylating agents - azacytidine and decitabine - which both achieve higher remission rates and show strong trends towards a prolonged OS

  3. Vorinostat in Treating Patients With Acute Myeloid Leukemia

    Science.gov (United States)

    2014-04-30

    Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  4. Genetics Home Reference: cytogenetically normal acute myeloid leukemia

    Science.gov (United States)

    ... normal acute myeloid leukemia Cytogenetically normal acute myeloid leukemia Printable PDF Open All Close All Enable Javascript ... expand/collapse boxes. Description Cytogenetically normal acute myeloid leukemia (CN-AML) is one form of a cancer ...

  5. Genetics Home Reference: core binding factor acute myeloid leukemia

    Science.gov (United States)

    ... acute myeloid leukemia Core binding factor acute myeloid leukemia Printable PDF Open All Close All Enable Javascript ... collapse boxes. Description Core binding factor acute myeloid leukemia (CBF-AML) is one form of a cancer ...

  6. Acute Myeloid Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  7. Extramedullary leukemia in children with acute myeloid leukemia

    DEFF Research Database (Denmark)

    Støve, Heidi Kristine; Sandahl, Julie Damgaard; Abrahamsson, Jonas

    2017-01-01

    BACKGROUND: The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified. PROCEDURE: This population-based study included 315 children from the NOPHO-AML 2004 trial. RESULTS: At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma...

  8. Biomarkers in Bone Marrow Samples From Pediatric Patients With High-Risk Acute Myeloid Leukemia

    Science.gov (United States)

    2016-05-17

    Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Childhood Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  9. Nucleophosmin 1 expression in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Mohammad Davoudi

    2015-09-01

    Full Text Available Nucleophosmin1 is a multifunctional protein that shuttles between nucleus and cytoplasm in some subtypes of acute myeloid leukemias. Mutated Nucleophosmin1 expresses aberrantly in the cytoplasm of the cell and transports from nucleolus to the cytoplasm. It is diagnosed by immunohistochemical techniques, flow cytometry assay and mutational analysis.The aim of this study is to evaluate the effects of Nucleophosmin1 mutation on the clinical presentations, prognosis, diagnosis and the treatment of acute myeloid leukemia. Thirteen articles were extracted from PubMed, Google scholar and Scopus in which the Nucleophosmin1 mutation correlated with gingival hyperplasia, high white blood cell count, lymphadenopathy, high platelet count and other signs and symptoms of myelomonocytic and monocytic acute myeloid leukemias. This mutation is a provisional entity in the classification of acute myeloid leukemia, which influences on the prognosis, clinical course and the treatment of some subtypes of acute myeloid leukemias. Nucleophosmin1 mutation has favorable prognostic value in the absence of other concomitant mutations.

  10. Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

    Science.gov (United States)

    2018-03-02

    Adult Acute Myeloid Leukemia in Remission; Acute Biphenotypic Leukemia; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm; Acute Myeloid Leukemia; Adult Acute Lymphoblastic Leukemia; Interleukin-3 Receptor Subunit Alpha Positive; Minimal Residual Disease; Refractory Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  11. Daunorubicin Hydrochloride, Cytarabine and Oblimersen Sodium in Treating Patients With Previously Untreated Acute Myeloid Leukemia

    Science.gov (United States)

    2013-06-04

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  12. Treatment strategies in acute myeloid leukemia

    NARCIS (Netherlands)

    Han Li-na, [No Value; Zhou Jin, [No Value; Schuringa, Jan Jacob; Vellenga, Edo

    2011-01-01

    Objective To summarize the risk stratification and current treatment strategies for acute myeloid leukemia (AML) and discuss the role of emerging novel agents that might be applied in future clinical trials. Data sources The data in this article were collected from PubMed database with relevant

  13. Recurrent Cytogenetic Abnormalities in Acute Myeloid Leukemia.

    Science.gov (United States)

    Yang, John J; Park, Tae Sung; Wan, Thomas S K

    2017-01-01

    The spectrum of chromosomal abnormality associated with leukemogenesis of acute myeloid leukemia (AML) is broad and heterogeneous when compared to chronic myeloid leukemia and other myeloid neoplasms. Recurrent chromosomal translocations such as t(8;21), t(15;17), and inv(16) are frequently detected, but hundreds of other uncommon chromosomal aberrations from AML also exist. This chapter discusses 22 chromosomal abnormalities that are common structural, numerical aberrations, and other important but infrequent (less than 1 %) translocations emphasized in the WHO classification. Brief morphologic, cytogenetic, and clinical characteristics are summarized, so as to provide a concise reference to cancer cytogenetic laboratories. Morphology based on FAB classification is used together with the current WHO classification due to frequent mentioning in a vast number of reference literatures. Characteristic chromosomal aberrations of other myeloid neoplasms such as myelodysplastic syndrome and myeloproliferative neoplasm will be discussed in separate chapters-except for certain abnormalities such as t(9;22) in de novo AML. Gene mutations detected in normal karyotype AML by cutting edge next generation sequencing technology are also briefly mentioned.

  14. Targeting MTHFD2 in acute myeloid leukemia.

    Science.gov (United States)

    Pikman, Yana; Puissant, Alexandre; Alexe, Gabriela; Furman, Andrew; Chen, Liying M; Frumm, Stacey M; Ross, Linda; Fenouille, Nina; Bassil, Christopher F; Lewis, Caroline A; Ramos, Azucena; Gould, Joshua; Stone, Richard M; DeAngelo, Daniel J; Galinsky, Ilene; Clish, Clary B; Kung, Andrew L; Hemann, Michael T; Vander Heiden, Matthew G; Banerji, Versha; Stegmaier, Kimberly

    2016-06-27

    Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decreased leukemia burden and prolonged survival. Based upon primary patient AML data and functional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppression. Mechanistically, MYC regulates the expression of MTHFD2, and MTHFD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTHFD2 in AML. © 2016 Pikman et al.

  15. Acute myeloid leukemia (AML) - children

    Science.gov (United States)

    Having a child with cancer can make you feel very alone. In a cancer support group, you can find people who are going ... Updated July 28, 2016. National Cancer Institute. www.cancer.gov/types/leukemia/patient/child-aml-treatment-pdq . Accessed August 3, 2016. Wei ...

  16. Acute myeloid leukemia: advances in diagnosis and classification.

    Science.gov (United States)

    Hasserjian, R P

    2013-06-01

    Acute myeloid leukemia is an aggressive myeloid neoplasm characterized by ≥20% myeloblasts in the blood or bone marrow. Current treatment strategies for acute myeloid leukemia are based on both patient-related parameters such as age and performance status as well as the intrinsic characteristics of particular disease subtypes. Subtyping of acute myeloid leukemia requires an integration of information from the patient's clinical history (such as any prior preleukemic myeloid neoplasm or cytotoxic potentially leukemogenic therapy), the leukemia morphology, cytogenetic findings, and the mutation status of particular genes (NPM1, FLT3, and CEBPA). In recent years, a barrage of information has become available regarding gene mutations that occur in acute myeloid leukemia and their influence on prognosis. Future therapies for acute myeloid leukemia will increasingly rely on the genetic signatures of individual leukemias and will adjust therapy to the predicted disease aggressiveness as well as employ therapies targeted against particular deregulated genetic pathways. This article reviews current standards for diagnosing and classifying acute myeloid leukemia according to the 2008 WHO Classification. Data that have subsequently accumulated regarding newly characterized gene mutations are also presented. It is anticipated that future leukemia classifications will employ a combination of karyotypic features and the gene mutation pattern to stratify patients to increasingly tailored treatment plans. © 2013 Blackwell Publishing Ltd.

  17. MicroRNA profiling can classify acute leukemias of ambiguous lineage as either acute myeloid leukemia or acute lymphoid leukemia.

    Science.gov (United States)

    de Leeuw, David C; van den Ancker, Willemijn; Denkers, Fedor; de Menezes, Renée X; Westers, Theresia M; Ossenkoppele, Gert J; van de Loosdrecht, Arjan A; Smit, Linda

    2013-04-15

    Classification of acute leukemia is based on the commitment of leukemic cells to the myeloid or the lymphoid lineage. However, a small percentage of acute leukemia cases lack straightforward immunophenotypical lineage commitment. These leukemias of ambiguous lineage represent a heterogeneous category of acute leukemia that cannot be classified as either acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL). The lack of clear classification of acute leukemias of ambiguous lineage as either AML or ALL is a hurdle in treatment choice for these patients. Here, we compared the microRNA (miRNA) expression profiles of 17 cases with acute leukemia of ambiguous lineage and 16 cases of AML, B-cell acute lymphoid leukemia (B-ALL), and T-cell acute lymphoid leukemia (T-ALL). We show that leukemias of ambiguous lineage do not segregate as a separate entity but exhibit miRNA expression profiles similar to AML, B-ALL, or T-ALL. We show that by using only 5 of the most lineage-discriminative miRNAs, we are able to define acute leukemia of ambiguous lineage as either AML or ALL. Our results indicate the presence of a myeloid or lymphoid lineage-specific genotype, as reflected by miRNA expression, in these acute leukemias despite their ambiguous immunophenotype. miRNA-based classification of acute leukemia of ambiguous lineage might be of additional value in therapeutic decision making.

  18. Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

    Science.gov (United States)

    2017-03-27

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  19. Emerging therapies for acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Caner Saygin

    2017-04-01

    Full Text Available Abstract Acute myeloid leukemia (AML is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH inhibitors, vadastuximab or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin, epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC inhibitors, bromodomain and extraterminal (BET inhibitors, FMS-like tyrosine kinase receptor 3 (FLT3 inhibitors, and antibody-drug conjugates (vadastuximab, as well as cell cycle inhibitors (volasertib, B-cell lymphoma 2 (BCL-2 inhibitors, and aminopeptidase inhibitors. These agents are actively undergoing clinical investigation alone or in combination with available chemotherapy.

  20. Current Management of Childhood Acute Myeloid Leukemia.

    Science.gov (United States)

    Rubnitz, Jeffrey E

    2017-02-01

    The outcome for children with acute myeloid leukemia (AML) has improved significantly over the past 30 years, with complete remission and overall survival rates exceeding 90 and 60%, respectively, in recent clinical trials. However, these improvements have not been achieved by the introduction of new agents. Instead, intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy have all contributed to this success. Nevertheless, novel therapies are needed, as the cure rates for many subtypes of childhood AML remain unacceptably low. Here, we briefly review advances in our understanding of the biology and genetics of AML, the results of recent clinical trials, and current recommendations for the treatment of children with AML.

  1. Molecular Genetic Markers in Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Sophia Yohe

    2015-03-01

    Full Text Available Genetics play an increasingly important role in the risk stratification and management of acute myeloid leukemia (AML patients. Traditionally, AML classification and risk stratification relied on cytogenetic studies; however, molecular detection of gene mutations is playing an increasingly important role in classification, risk stratification, and management of AML. Molecular testing does not take the place of cytogenetic testing results, but plays a complementary role to help refine prognosis, especially within specific AML subgroups. With the exception of acute promyelocytic leukemia, AML therapy is not targeted but the intensity of therapy is driven by the prognostic subgroup. Many prognostic scoring systems classify patients into favorable, poor, or intermediate prognostic subgroups based on clinical and genetic features. Current standard of care combines cytogenetic results with targeted testing for mutations in FLT3, NPM1, CEBPA, and KIT to determine the prognostic subgroup. Other gene mutations have also been demonstrated to predict prognosis and may play a role in future risk stratification, although some of these have not been confirmed in multiple studies or established as standard of care. This paper will review the contribution of cytogenetic results to prognosis in AML and then will focus on molecular mutations that have a prognostic or possible therapeutic impact.

  2. Genetics of therapy-related myelodysplasia and acute myeloid leukemia

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, J.; Andersen, Mette Klarskov; Andersen, M.T.

    2008-01-01

    Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according...

  3. Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

    NARCIS (Netherlands)

    F.P.G. Silva (Fernando); I. Almeida (Inês); B. Morolli (Bruno); G. Brouwer-Mandema (Geeske); H. Wessels (Hans); R. Vossen (Rolf); H. Vrieling (Harry); E.W.A. Marijt (Erik); P.J.M. Valk (Peter); J.C. Kluin-Nelemans (Hanneke); W.R. Sperr (Wolfgang); W.D. Ludwig; M. Giphart-Gassler (Micheline)

    2009-01-01

    textabstractBackground: Minimally differentiated acute myeloid leukemia is heterogeneous in karyotype and is defined by immature morphological and molecular characteristics. This originally French-American-British classification is still used in the new World Health Organization classification when

  4. Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

    NARCIS (Netherlands)

    Silva, Fernando P. G.; Almeida, Ines; Morolli, Bruno; Brouwer-Mandema, Geeske; Wessels, Hans; Vossen, Rolf; Vrieling, Harry; Marijt, Erik W. A.; Valk, Peter J. M.; Kluin-Nelemans, Hanneke C.; Sperr, Wolfgang R.; Ludwig, Wolf-Dieter; Giphart-Gassler, Micheline

    2009-01-01

    Background Minimally differentiated acute myeloid leukemia is heterogeneous in karyotype and is defined by immature morphological and molecular characteristics. This originally French-American-British classification is still used in the new World Health Organization classification when other

  5. Genetics of therapy-related myelodysplasia and acute myeloid leukemia

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, J.; Andersen, Mette Klarskov; Andersen, M.T.

    2008-01-01

    Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according to cytog......Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according...

  6. Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8 Followed by Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

    Science.gov (United States)

    2018-03-19

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Secondary Acute Myeloid Leukemia

  7. ERYTHEMA NODOSUM REVEALING ACUTE MYELOID LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Chebbi Wafa

    2013-07-01

    Full Text Available Introduction: Erythema nodosum (EN is the most common type of panniculitis. It may be idiopathic or secondary to various etiologies. However, the occurrence of erythema nodosum in malignant hemopathy had rarely been reported. Case report: A 42 year-old woman presented with a four week history of recurrent multiple painful erythematous nodules developed on the lower limbs associated with arthralgia of the ankles and fever. The clinical features of skin lesions with contusiform color evolution allowed establishing the diagnosis of EN. No underlying cause was found. The skin lesions were improved with non-steroidal anti-inflammatory drugs and colchicine. Three months later, the patient consulted for recurrence of EN associated with fever, inflammatory polyarthralgia and hepatosplenomegaly. The peripheral blood count revealed pancytopenia. A bone marrow examination confirmed the diagnosis of acute myeloid leukemia type 2. Initiation of chemotherapy was followed by the complete disappearance of skin lesions of EN. Conclusion: Paraneoplastic erythema nodosum is a rare entity. In the literature, a few cases of association with leukemia have been reported. Exploration for solid neoplasms or hemopathy in case of recurrent EN or resistance to conventional treatment should be systematic

  8. Translational Studies in Elderly Patients with Acute Myeloid Leukemia

    NARCIS (Netherlands)

    B. van der Holt (Bronno)

    2007-01-01

    textabstractThe production of blood cells (hematopoiesis) takes place in the bone marrow. Acute myeloid leukemia (AML) is a clonal disease, which is characterized by an increase in the number of myeloid cells in the bone marrow and an arrest in their maturation. This frequently results in a severe

  9. Identification of de Novo Fanconi Anemia in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

    Science.gov (United States)

    2016-05-13

    Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Fanconi Anemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  10. The Epigenetic Landscape of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Emma Conway O’Brien

    2014-01-01

    Full Text Available Acute myeloid leukemia (AML is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.

  11. Novel therapeutic options in Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Michael Medinger

    2016-01-01

    Full Text Available Acute myeloid leukemia (AML is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence is increasing as the population ages. Cytogenetic anomalies and mutation testing remain important prognostic tools for tailoring treatment after induction therapy. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, as well as the rapid development of new drugs, standard treatment options have not experienced major changes during the past three decades. Especially for patients with intermediate or high-risk AML, which often show relapse. Allogeneic hematopoietic stem cell transplantation (HSCT remains the best chance for cure. Here we review the state of the art therapy of AML, with special focus on new developments in immunotherapies and cellular therapies including HSCT and particularly discuss the impact of new conditioning and haplo-identical donor regimens for HSCT, post-transplant strategies for preventing and treating relapse, and emerging novel therapeutic options.

  12. Unfavorable-risk acute myeloid leukemia dissected.

    Science.gov (United States)

    Strickland, Stephen A; Mohan, Sanjay R; Savona, Michael R

    2016-03-01

    Acute myeloid leukemia (AML) is an immensely heterogeneous disease based on the presence of varying combinations of morphologic, immunophenotypic, genetic, and molecular characteristics identified among those diagnosed with this disease. Although current therapeutic strategies provide a reasonable likelihood of achieving a complete remission for the majority of patients, relapse rates and subsequent disease-related mortality remain unacceptably high. Improved methods of risk stratification are needed to better identify patients at considerable risk of relapse in hopes of allowing for early therapeutic intervention and/or intensification that may lead to a higher likelihood of cure. The current status of risk stratification of AML and emerging technologies with potential to improve prognostic classification and outcomes are summarized in this review. Refinement of our understanding of the impact of current pretreatment AML cytogenetic, immunophenotypic, and molecular aberrations to predict outcomes and guide therapeutic decision-making is ongoing. Emerging data suggest that incorporation of the degree of posttreatment response and/or the detection of minimal residual disease can improve the accuracy of risk stratification for individual patients. Although pretreatment disease characteristics remain the hallmark of prognostication for AML patients, posttreatment parameters such as minimal residual disease assessment and degree of response to therapy possess the ability to further refine our identification of patients with unfavorable disease and thereby influence decisions regarding therapeutic planning.

  13. Alternative Donor Transplantation for Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Nelli Bejanyan

    2015-06-01

    Full Text Available Allogeneic hematopoietic cell transplantation (allo-HCT is a potentially curative therapy for adult patients with acute myeloid leukemia (AML, but its use for consolidation therapy after first remission with induction chemotherapy used to be limited to younger patients and those with suitable donors. The median age of AML diagnosis is in the late 60s. With the introduction of reduced-intensity conditioning (RIC, many older adults are now eligible to receive allo-HCT, including those who are medically less fit to receive myeloablative conditioning. Furthermore, AML patients commonly have no human leukocyte antigen (HLA-identical or medically suitable sibling donor available to proceed with allo-HCT. Technical advances in donor matching, suppression of alloreactivity, and supportive care have made it possible to use alternative donors, such as unrelated umbilical cord blood (UCB and partially HLA-matched related (haploidentical donors. Outcomes after alternative donor allo-HCT are now approaching the outcomes observed for conventional allo-HCT with matched related and unrelated donors. Thus, with both UCB and haploidentical donors available, lack of donor should rarely be a limiting factor in offering an allo-HCT to adults with AML.

  14. MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    Science.gov (United States)

    2017-12-04

    Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia

  15. [Myeloid/natural killer cell precursor and myeloid/natural killer cell acute leukemia].

    Science.gov (United States)

    Ni, Ming; Chen, Bao-An

    2014-04-01

    With the popularity of flow cytometry, the classification of leukemia become more detailed. Myeloid/natural killer cell precursor acute leukemia and myeloid/natural killer cell acute leukemias are generally recognized as two kinds of rare leukemias and have poor prognosis. The cells expressed both myeloid and lymphatic antigens in these two leukemia and can not be diagnosed by morphology. The only basis to make a definite diagnosis is their unique Immunophenotyping. The role of CD7 and CD56 in these two leukemia are compelling, in the other hand, as the progress of cell differentiation research, there are many new awareness of NK cell differentiation. In this article, the biological origin, clinical manifestation, diagnosis, treatment and the role of CD7 and CD56 in these two leukemia are briefly summarized.

  16. Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    Science.gov (United States)

    2017-06-27

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia

  17. Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes

    Science.gov (United States)

    2018-03-05

    Acute Biphenotypic Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Blasts Under 10 Percent of Bone Marrow Nucleated Cells; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Mixed Phenotype Acute Leukemia; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Pancytopenia; Refractory Anemia; Secondary Acute Myeloid Leukemia

  18. Reproducibility and prognostic significance of morphologic dysplasia in de novo acute myeloid leukemia.

    Science.gov (United States)

    Weinberg, Olga K; Pozdnyakova, Olga; Campigotto, Federico; DeAngelo, Daniel J; Stone, Richard M; Neuberg, Donna; Hasserjian, Robert P

    2015-07-01

    The 2008 WHO classification of acute myeloid leukemia includes a category of acute myeloid leukemia with myelodysplasia-related changes; however, the significance of multilineage dysplasia alone is controversial and its reproducibility has not been evaluated in acute myeloid leukemia. We performed an in-depth analysis of morphologic dysplasia in 159 de novo acute myeloid leukemia cases lacking myelodysplasia-related cytogenetic abnormalities. Using the 2008 WHO criteria, there were 89 acute myeloid leukemia-not otherwise specified (56%) and 43 acute myeloid leukemia with myelodysplasia-related changes (27%), while 27 cases were ambiguous as to myelodysplasia-related changes status due to limited maturing cells (acute myeloid leukemia-not evaluable, 17%). On multivariable analysis, neither acute myeloid leukemia with myelodysplasia-related changes nor acute myeloid leukemia-not evaluable showed significantly different event-free survival compared with acute myeloid leukemia-not otherwise specified in the 137 patients treated with induction chemotherapy. When individual dysplastic features were analyzed, only micromegakaryocytes and hypogranulated myeloid cells emerged as factors significantly associated with shorter event-free survival in a multivariable analysis that included the other significant covariates of age, white blood count, platelet count, abnormal karyotype and stem-cell transplantation. Our findings indicate that the current 2008 WHO definition of multilineage dysplasia in acute myeloid leukemia in its current form is not optimal, and that the use of a more restricted definition of morphologic dysplasia results in more relevant risk stratification that is independent of other conventional prognostic factors.

  19. BCL11A expression in acute phase chronic myeloid leukemia.

    Science.gov (United States)

    Yin, Jiawei; Zhang, Fan; Tao, Huiquan; Ma, Xiao; Su, Guangsong; Xie, Xiaoli; Xu, Zhongjuan; Zheng, Yanwen; Liu, Hong; He, Chao; Mao, Zhengwei Jenny; Wang, Zhiwei; Chang, Weirong; Gale, Robert Peter; Wu, Depei; Yin, Bin

    2016-08-01

    Chronic myeloid leukemia (CML) has chronic and acute phases. In chronic phase myeloid differentiation is preserved whereas in acute phase myeloid differentiation is blocked. Acute phase CML resembles acute myeloid leukemia (AML). Chronic phase CML is caused by BCR-ABL1. What additional mutation(s) cause transition to acute phase is unknown and may differ in different persons with CML. BCL11A encodes a transcription factor and is aberrantly-expressed in several haematological and solid neoplasms. We analyzed BCL11A mRNA levels in subjects with chronic and acute phase CML. BCL11A transcript levels were increased in subjects with CML in acute phase compared with those in normals and in subjects in chronic phase including some subjects studied in both phases. BCL11A mRNA levels were correlated with percent bone marrow blasts and significantly higher in lymphoid versus myeloid blast crisis. Differentiation of K562 with butyric acid, a CML cell line, decreased BCL11A mRNA levels. Cytology and flow cytometry analyses showed that ectopic expression of BCL11A in K562 cells blocked differentiation. These data suggest BCL11A may operate in transformation of CML from chronic to acute phase in some persons. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Cutaneous myeloid sarcoma: natural history and biology of an uncommon manifestation of acute myeloid leukemia.

    Science.gov (United States)

    Hurley, M Yadira; Ghahramani, Grant K; Frisch, Stephanie; Armbrecht, Eric S; Lind, Anne C; Nguyen, Tudung T; Hassan, Anjum; Kreisel, Friederike H; Frater, John L

    2013-05-01

    We conducted a retrospective study of patients with cutaneous myeloid sarcoma, from 2 tertiary care institutions. Eighty-three patients presented, with a mean age of 52 years. Diagnosis of myeloid sarcoma in the skin was difficult due to the low frequency of myeloperoxidase and/or CD34+ cases (56% and 19% of tested cases, respectively). Seventy-one of the 83 patients (86%) had ≥ 1 bone marrow biopsy. Twenty-eight (39%) had acute myeloid leukemia with monocytic differentiation. Twenty-three had other de novo acute myeloid leukemia subtypes. Thirteen patients had other myeloid neoplasms, of which 4 ultimately progressed to an acute myeloid leukemia. Seven had no bone marrow malignancy. Ninety-eight percent of the patients received chemotherapy, and approximately 89% died of causes related to their disease. Cutaneous myeloid sarcoma in most cases represents an aggressive manifestation of acute myeloid leukemia. Diagnosis can be challenging due to lack of myeloblast-associated antigen expression in many cases, and difficulty in distinguishing monocyte-lineage blasts from neoplastic and non-neoplastic mature monocytes.

  1. Ploidy and clinical characteristics of childhood acute myeloid leukemia

    DEFF Research Database (Denmark)

    Sandahl, Julie Damgaard; Kjeldsen, Eigil; Abrahamsson, Jonas

    2014-01-01

    We report the first large series (n = 596) of pediatric acute myeloid leukemia (AML) focusing on modal numbers (MN) from the population-based NOPHO-AML trials. Abnormal karyotypes were present in 452 cases (76%) and numerical aberrations were present in 40% (n = 237) of all pediatric AML. Among...

  2. Occupational exposure to solvents and acute myeloid leukemia

    DEFF Research Database (Denmark)

    Talibov, Madar; Lehtinen-Jacks, Susanna; Martinsen, Jan Ivar

    2014-01-01

    OBJECTIVE: The aim of the current study was to assess the relation between occupational exposure to solvents and the risk of acute myeloid leukemia (AML). METHODS: Altogether, this study comprises 15 332 incident cases of AML diagnosed in Finland, Norway, Sweden and Iceland from 1961-2005 and 76...

  3. Diagnostic work-up of acute myeloid leukemia.

    Science.gov (United States)

    Weinberg, Olga K; Sohani, Aliyah R; Bhargava, Parul; Nardi, Valentina

    2017-03-01

    Acute myeloid leukemia (AML) is characterized by a clonal expansion of undifferentiated myeloid precursors resulting in impaired hematopoiesis and bone marrow failure. In 2016, the World Health Organization (WHO) published revisions to the classification of myeloid neoplasms and acute leukemias. Similar to the 2008 classification, the updated classification incorporates clinical features, morphology, immunophenotyping, and cytogenetics, with greater emphasis on molecular genetics, to define disease entities. This brief review addresses the various components of pathologic assessment to establish a diagnosis of AML and to help risk stratify patients, with an emphasis on newer techniques used in the detection of mutations with prognostic significance, as well as assays employed in the evaluation of minimal residual disease following treatment. © 2017 Wiley Periodicals, Inc.

  4. A case report of acute myeloid leukemia and neurofibromatosis 1

    Directory of Open Access Journals (Sweden)

    Chiara Sartor

    2013-07-01

    Full Text Available We report a case of a 65-year old patient affected by neurofibromatosis 1, documented by the presence of germ-line mutation on the NF1 gene, who developed various hyperproliferative malignant and benign diseases. He was brought to our attention for the diagnosis of acute myeloid leukemia revealed by major fatigue and dyspnea. The disease characteristics at diagnosis were hyperleukocytosis and complex karyotype with the inversion of the chromosome 16, classifying as a high-risk leukemia. The association between leukemia and neurofibromatosis 1 is controversial and needs to be further investigated. Nevertheless, such patients present a wide number of comorbidities that make therapeutic strategies most difficult.

  5. A reevaluation of erythroid predominance in Acute Myeloid Leukemia using the updated WHO 2016 Criteria.

    Science.gov (United States)

    Margolskee, Elizabeth; Mikita, Geoff; Rea, Bryan; Bagg, Adam; Zuo, Zhuang; Sun, Yi; Goswami, Maitrayee; Wang, Sa A; Oak, Jean; Arber, Daniel A; Allen, M Brandon; George, Tracy I; Rogers, Heesun J; Hsi, Eric; Hasserjian, Robert P; Orazi, Attilio

    2018-02-05

    The 2016 WHO update changed the diagnostic criteria for myeloid neoplasms with erythroid predominance, limiting the diagnosis of acute myeloid leukemia to cases with ≥20% blasts in the bone marrow or peripheral blood. Although acute myeloid leukemia with ≥50% erythroid cells has historically been presumed to represent acute myeloid leukemia with myelodysplasia-related changes, this hypothesis has never been systematically examined. We sought to investigate the clinicopathologic, cytogenetic, and molecular features of acute myeloid leukemia with erythroid predominance to subclassify cases as defined by the 2016 WHO. We retrospectively identified patients with ≥50% erythroid precursors and either ≥20% bone marrow blasts or ≥20% peripheral blood blasts at the time of initial diagnosis at seven major academic centers. Laboratory and clinical data were obtained. Patients were then reclassified according to 2016 WHO guidelines. A matched control group was also obtained. We identified 146 patients with acute myeloid leukemia with erythroid predominance (62% M, average age: 62 y, range: 5-93 y). Of these, 91 were acute myeloid leukemia with myelodysplasia-related changes, 20 (14%) were therapy-related myeloid neoplasm, 23 (16%) acute myeloid leukemia, not otherwise specified, and ten acute myeloid leukemia with recurrent cytogenetic/molecular abnormalities. The bone marrow blast count ranged from 9-41%. There was no difference in survival for patients with erythroid predominance compared to patients with acute myeloid leukemia without erythroid proliferations. In a multivariable analysis, cytogenetic risk was the only significant predictor of survival. We find a significantly lower rate of FLT3 and RAS pathway alterations in acute myeloid leukemia with erythroid predominance compared to controls. Our study is one of the first to apply the 2016 WHO guidelines for classification of acute myeloid leukemia. We find acute myeloid leukemia with erythroid

  6. Recombinant EphB4-HSA Fusion Protein and Azacitidine or Decitabine for Relapsed or Refractory Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Patients Previously Treated With a Hypomethylating Agent

    Science.gov (United States)

    2017-08-18

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Recurrent Adult Acute Myeloid Leukemia

  7. Recurrence of acute myeloid leukemia in cryptorchid testis: case report

    Energy Technology Data Exchange (ETDEWEB)

    Góes, Luccas Santos Patto de [Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP (Brazil); Lopes, Roberto Iglesias [Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP (Brazil); Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Campos, Octavio Henrique Arcos [Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP (Brazil); Oliveira, Luiz Carlos Neves de; Sant' Anna, Alexandre Crippa; Dall' Oglio, Marcos Francisco; Srougi, Miguel [Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-07-01

    A 23-year-old male with a history of bone marrow transplant for acute myeloid leukemia. He presented a large mass in the right inguinal region 5 years ago. Upon physical examination, right-sided cryptorchidism was observed. The tumor markers alpha-fetoprotein and beta-HCG were within normalcy range and lactate dehydrogenase was raised. Computed tomography of the abdomen and pelvis revealed right testicular mass in contiguity with the inguinal canal to the ipsilateral retroperitoneum, associated with right hydronephrosis. Due to the risk of germ-cell tumor in undescended testicle, the patient underwent radical right orchiectomy. The pathological examination showed recurrence of acute myeloid leukemia in the testis. He was referred to oncology for adjuvant therapy. Our literature review found no similar cases described.

  8. Recurrence of acute myeloid leukemia in cryptorchid testis: case report

    OpenAIRE

    Góes, Luccas Santos Patto de; Lopes, Roberto Iglesias; Campos, Octavio Henrique Arcos; Oliveira, Luiz Carlos Neves de; Sant’Anna, Alexandre Crippa; Dall’Oglio, Marcos Francisco; Srougi, Miguel

    2014-01-01

    A 23-year-old male with a history of bone marrow transplant for acute myeloid leukemia. He presented a large mass in the right inguinal region 5 years ago. Upon physical examination, right-sided cryptorchidism was observed. The tumor markers alpha-fetoprotein and beta-HCG were within normalcy range and lactate dehydrogenase was raised. Computed tomography of the abdomen and pelvis revealed right testicular mass in contiguity with the inguinal canal to the ipsilateral retroperitoneum, associat...

  9. Allogeneic stem cell transplantation in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Natasha Ali

    2012-11-01

    Full Text Available We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients. Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

  10. Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells

    Directory of Open Access Journals (Sweden)

    Yahui Ding

    2016-09-01

    Full Text Available Abstract Background The poor outcomes for patients diagnosed with acute myeloid leukemia (AML are largely attributed to leukemia stem cells (LSCs which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity. Methods The aim of the present study was to identify alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of alantolactone in vitro and in vivo. Results The present study is the first to demonstrate that alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C, alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-alantolactone, a water-soluble prodrug of alantolactone, could suppress tumor growth in vivo. Conclusions Based on these results, we propose that alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents.

  11. General Information about Adult Acute Myeloid Leukemia

    Science.gov (United States)

    ... used to determine if the leukemia has spread: Lumbar puncture : A procedure used to collect a sample of cerebrospinal fluid (CSF) from the spinal column . This is done by placing a needle between ...

  12. Treatment Option Overview (Adult Acute Myeloid Leukemia)

    Science.gov (United States)

    ... used to determine if the leukemia has spread: Lumbar puncture : A procedure used to collect a sample of cerebrospinal fluid (CSF) from the spinal column . This is done by placing a needle between ...

  13. Treatment Options for Adult Acute Myeloid Leukemia

    Science.gov (United States)

    ... used to determine if the leukemia has spread: Lumbar puncture : A procedure used to collect a sample of cerebrospinal fluid (CSF) from the spinal column . This is done by placing a needle between ...

  14. Stages of Adult Acute Myeloid Leukemia

    Science.gov (United States)

    ... used to determine if the leukemia has spread: Lumbar puncture : A procedure used to collect a sample of cerebrospinal fluid (CSF) from the spinal column . This is done by placing a needle between ...

  15. Acute Myeloid Leukemia (AML) (For Parents)

    Science.gov (United States)

    ... fluid (CSF, the fluid surrounding the brain and spinal cord) for examination in a lab. Flow cytometry tests. Using markers on leukemia cells collected from the blood, bone marrow, and/or CSF, doctors can determine the type ...

  16. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate

    DEFF Research Database (Denmark)

    Abrahamsson, Jonas; Forestier, Erik; Heldrup, Jesper

    2011-01-01

    To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course.......To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course....

  17. Azelaic Acid Exerts Antileukemic Activity in Acute Myeloid Leukemia.

    Science.gov (United States)

    Pan, Yunbao; Liu, Dong; Wei, Yongchang; Su, Dan; Lu, Chenyang; Hu, Yanchao; Zhou, Fuling

    2017-01-01

    Acute myeloid leukemia (AML) is an acute leukemia common in most adults; its prevalence intensifies with age. The overall survival of AML is very poor because of therapeutic resistance. Azelaic acid (AZA) is non-toxic, non-teratogenic, and non-mutagenic and its antitumor effect on various tumor cells is well established; Nonetheless, its therapeutic effects in AML cells are largely unknown. In this study, it was shown that AZA significantly inhibits the cell viability and induces apoptosis in AML cells in a dose-dependent manner. Additionally, AZA suppressed the expression of phosphorylated Akt, Jab1 and Trx, and this suppression was enhanced by treatment with Jab1 siRNA. Furthermore, AZA sensitized AML cells to Ara-c chemotherapy. The suppressive effect of AZA on tumor growth was examined in vivo by subcutaneously inoculated AML cells in a tumor model using nude mice. These findings indicate that AZA is useful as an effective ingredient in antineoplastic activity.

  18. Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia.

    Science.gov (United States)

    Zwaan, C Michel; Kolb, Edward A; Reinhardt, Dirk; Abrahamsson, Jonas; Adachi, Souichi; Aplenc, Richard; De Bont, Eveline S J M; De Moerloose, Barbara; Dworzak, Michael; Gibson, Brenda E S; Hasle, Henrik; Leverger, Guy; Locatelli, Franco; Ragu, Christine; Ribeiro, Raul C; Rizzari, Carmelo; Rubnitz, Jeffrey E; Smith, Owen P; Sung, Lillian; Tomizawa, Daisuke; van den Heuvel-Eibrink, Marry M; Creutzig, Ursula; Kaspers, Gertjan J L

    2015-09-20

    Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects. © 2015 by American Society of Clinical Oncology.

  19. Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia

    Science.gov (United States)

    Zwaan, C. Michel; Kolb, Edward A.; Reinhardt, Dirk; Abrahamsson, Jonas; Adachi, Souichi; Aplenc, Richard; De Bont, Eveline S.J.M.; De Moerloose, Barbara; Dworzak, Michael; Gibson, Brenda E.S.; Hasle, Henrik; Leverger, Guy; Locatelli, Franco; Ragu, Christine; Ribeiro, Raul C.; Rizzari, Carmelo; Rubnitz, Jeffrey E.; Smith, Owen P.; Sung, Lillian; Tomizawa, Daisuke; van den Heuvel-Eibrink, Marry M.; Creutzig, Ursula; Kaspers, Gertjan J.L.

    2015-01-01

    Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML—supportive care—and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects. PMID:26304895

  20. Esophageal Candidiasis as the Initial Manifestation of Acute Myeloid Leukemia.

    Science.gov (United States)

    Komeno, Yukiko; Uryu, Hideki; Iwata, Yuko; Hatada, Yasumasa; Sakamoto, Jumpei; Iihara, Kuniko; Ryu, Tomiko

    2015-01-01

    A 47-year-old woman presented with persistent dysphagia. A gastroendoscopy revealed massive esophageal candidiasis, and oral miconazole was prescribed. Three weeks later, she returned to our hospital without symptomatic improvement. She was febrile, and blood tests showed leukocytosis (137,150 /μL, blast 85%), anemia and thrombocytopenia. She was diagnosed with acute myeloid leukemia (AML). She received chemotherapy and antimicrobial agents. During the recovery from the nadir, bilateral ocular candidiasis was detected, suggesting the presence of preceding candidemia. Thus, esophageal candidiasis can be an initial manifestation of AML. Thorough examination to detect systemic candidiasis is strongly recommended when neutropenic patients exhibit local candidiasis prior to chemotherapy.

  1. Comorbidity and performance status in acute myeloid leukemia patients

    DEFF Research Database (Denmark)

    Østgård, Lene Sofie Granfeldt; Nørgaard, J M; Sengeløv, H

    2015-01-01

    As the world population ages, the comorbidity burden in acute myeloid leukemia (AML) patients increases. Evidence on how to integrate comorbidity measures into clinical decision-making is sparse. We determined the prognostic impact of comorbidity and World Health Organization Performance Status (...... with an increased short- and long-term mortality (adjusted 90 day MR, PS⩾2=3.43 (95%CI=2.30-5.13); adjusted 91 day-3 year MR=1.35 (95%CI=1.06-1.74)). We propose that more patients with comorbidity may benefit from intensive chemotherapy....

  2. Complexity on Acute Myeloid Leukemia mRNA Transcript Variant

    Directory of Open Access Journals (Sweden)

    Carlo Cattani

    2011-01-01

    Full Text Available This paper deals with the sequence analysis of acute myeloid leukemia mRNA. Six transcript variants of mlf1 mRNA, with more than 2000 bps, are analyzed by focusing on the autocorrelation of each distribution. Through the correlation matrix, some patches and similarities are singled out and commented, with respect to similar distributions. The comparison of Kolmogorov fractal dimension will be also given in order to classify the six variants. The existence of a fractal shape, patterns, and symmetries are discussed as well.

  3. Genital Infection as a First Sign of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Naoki Oiso

    2010-02-01

    Full Text Available Fournier’s gangrene is a life-threatening disorder caused by aerobic and anaerobic bacterial infection. We report a case of genital infection as the initial warning sign of acute myeloid leukemia. We were able to prevent progression to Fournier’s gangrene in our patient by immediate intensive therapy with incision, blood transfusions and intravenous administration of antibiotics. This case suggests that hematologists and dermatologists should keep in mind that genital infection can be a first sign of hematologic malignancy.

  4. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    Science.gov (United States)

    2014-08-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma

  5. The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia.

    Science.gov (United States)

    Balgobind, B V; Zwaan, C M; Pieters, R; Van den Heuvel-Eibrink, M M

    2011-08-01

    Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

  6. Rare cytogenetic abnormalities and alteration of microRNAs in acute myeloid leukemia and response to therapy

    OpenAIRE

    Mohammad Shahjahani; Elham Khodadi; Mohammad Seghatoleslami; Javad Mohammadi Asl; Neda Golchin; Zeynab Deris Zaieri; Najmaldin Saki

    2015-01-01

    Acute myeloid leukemia (AML) is the most common acute leukemia in adults, which is heterogeneous in terms of morphological, cytogenetic and clinical features. Cytogenetic abnormalities, including karyotype aberrations, gene mutations and gene expression abnormalities are the most important diagnostic tools in diagnosis, classification and prognosis in acute myeloid leukemias. Based on World Health Organization (WHO) classification, acute myeloid leukemias can be divided to four groups. Due to...

  7. Genomics of Acute Myeloid Leukemia Diagnosis and Pathways.

    Science.gov (United States)

    Bullinger, Lars; Döhner, Konstanze; Döhner, Hartmut

    2017-03-20

    In recent years, our understanding of the molecular pathogenesis of myeloid neoplasms, including acute myeloid leukemia (AML), has been greatly advanced by genomics discovery studies that use novel high-throughput sequencing techniques. AML, similar to most other cancers, is characterized by multiple somatically acquired mutations that affect genes of different functional categories, a complex clonal architecture, and disease evolution over time. Patterns of mutations seem to follow specific and temporally ordered trajectories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. The same genes are frequently found to be mutated in elderly individuals along with clonal expansion of hematopoiesis that confers an increased risk for the development of hematologic cancers. Furthermore, such mutations may persist after therapy, lead to clonal expansion during hematologic remission, and eventually lead to relapsed disease. In contrast, mutations involving NPM1 or signaling molecules (eg, FLT3, RAS) typically are secondary events that occur later during leukemogenesis. Genetic data are now being used to inform disease classification, risk stratification, and clinical care of patients. Two new provisional entities, AML with mutated RUNX1 and AML with BCR- ABL1, have been included in the current update of the WHO classification of myeloid neoplasms and AML, and mutations in three genes- RUNX1, ASXL1, and TP53-have been added in the risk stratification of the 2017 European LeukemiaNet recommendations for AML. Integrated evaluation of baseline genetics and assessment of minimal residual disease are expected to further improve risk stratification and selection of postremission therapy. Finally, the identification of disease alleles will guide the development and use of novel molecularly targeted therapies.

  8. Diagnosis of acute myeloid leukemia in a dental hospital; report of a ...

    African Journals Online (AJOL)

    2014-10-10

    Oct 10, 2014 ... [1]. Acute myeloid leukemia (AML) can present as leukemic infiltrates in many sites including gingival enlargement, mucosal and skin nodules.[5] Oral lesions occur both in acute and chronic forms of all types of leukemias, however, oral manifestations are more common in the acute stages of the disease.

  9. CD117 expression on blast cells in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Goryainova N.V.

    2015-09-01

    Full Text Available The aim of the present work was to analyze the frequency of CD117 (c-KIT antigen expression on the blast cells in acute myeloid leukemia (AML, evaluation of the presence of the relationship between the expression of the c-KIT and leukemia according to the FAB classification and definition of co-expression of the antigen CD117, antigens CD33 and CD34. The data of 47 patients with AML were diagnosed. M0 AML variant was established in 3 (6% patients, M1 – in 2 (4%, M2 – in 9 (20%, M4 – in 22 (47% and M5 – in 11 (23%. For immunophenotypic stu¬dies monoclonal antibodies (mAb that detect antigens of anti-CD34, anti-CD33 and anti-CD117 (Becton Dickinson, USA were used. The presence of the antigen CD117 was detected in 39 people, accounting for 83% of all surveyed. Antigen c-KIT was present in 48.117.0% cells on average: in all 3 cases – AML M0, in2 cases of AML M1, in 6 cases – AML M2, 20 of 22 cases – AML M4 and in 8 of 11 AML M5 cases. Average levels of CD117 in investigated leukemia cases statistically differed significantly (p=0.0067. Among 39 CD117- positive patients in 25 (53% co-expression of CD117+/CD34+ was revealed. Expression of CD117+/CD34- was observed in 14 cases (30%, CD117-/CD34+ – in 4 cases (8,5%, CD117-/CD34- – in 4 cases (8.5%. CD34 had of 64% of cells of myeloid origin. A high positive cor¬relation between expression of CD117 and CD34 (r=+0,5169 was determined, being statistically significant (p0,0067.

  10. Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors

    Science.gov (United States)

    Sukhai, Mahadeo A.; Prabha, Swayam; Hurren, Rose; Rutledge, Angela C.; Lee, Anna Y.; Sriskanthadevan, Shrivani; Sun, Hong; Wang, Xiaoming; Skrtic, Marko; Seneviratne, Ayesh; Cusimano, Maria; Jhas, Bozhena; Gronda, Marcela; MacLean, Neil; Cho, Eunice E.; Spagnuolo, Paul A.; Sharmeen, Sumaiya; Gebbia, Marinella; Urbanus, Malene; Eppert, Kolja; Dissanayake, Dilan; Jonet, Alexia; Dassonville-Klimpt, Alexandra; Li, Xiaoming; Datti, Alessandro; Ohashi, Pamela S.; Wrana, Jeff; Rogers, Ian; Sonnet, Pascal; Ellis, William Y.; Corey, Seth J.; Eaves, Connie; Minden, Mark D.; Wang, Jean C.Y.; Dick, John E.; Nislow, Corey; Giaever, Guri; Schimmer, Aaron D.

    2012-01-01

    Despite efforts to understand and treat acute myeloid leukemia (AML), there remains a need for more comprehensive therapies to prevent AML-associated relapses. To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the antimalarial agent mefloquine as a compound that selectively kills AML cells and AML stem cells in a panel of leukemia cell lines and in mice. Using a yeast genome-wide functional screen for mefloquine sensitizers, we identified genes associated with the yeast vacuole, the homolog of the mammalian lysosome. Consistent with this, we determined that mefloquine disrupts lysosomes, directly permeabilizes the lysosome membrane, and releases cathepsins into the cytosol. Knockdown of the lysosomal membrane proteins LAMP1 and LAMP2 resulted in decreased cell viability, as did treatment of AML cells with known lysosome disrupters. Highlighting a potential therapeutic rationale for this strategy, leukemic cells had significantly larger lysosomes compared with normal cells, and leukemia-initiating cells overexpressed lysosomal biogenesis genes. These results demonstrate that lysosomal disruption preferentially targets AML cells and AML progenitor cells, providing a rationale for testing lysosomal disruption as a novel therapeutic strategy for AML. PMID:23202731

  11. [Treatment of acute myeloid leukemia -- a single center experience (2007-2013)].

    Science.gov (United States)

    Selmeczi, Anna; Udvardy, Miklós; Illés, Arpád; Telek, Béla; Kiss, Attila; Batár, Péter; Reményi, Gyula; Szász, Róbert; Ujj, Zsófia; Márton, Adrienn; Ujfalusi, Anikó; Hevessy, Zsuzsanna; Pinczés, László; Bedekovics, Judit; Rejtő, László

    2014-04-27

    Mortality of acute myeloid leukemia is still 60-70% in young (myeloid leukemia. From 2007 to 2013, 173 patients with acute myeloid leukemia were treated. Patients were classified according to the European LeukemiaNet prognostic guideline. Association between mortality and the type of acute myeloid leukemia (secondary or primary), dose of daunoblastin at induction of treatment, and the rate of minimal residual disease were investigated. The 5-year survival probability was 25% in young adults and 2% in the elderly. The survival was significantly influenced by these prognostic factors. The 5-year survival rate was 50% in the young, favorable prognostic group. The 90 mg/m2 daunoblastin dose was found to be beneficial. Addition of bortezomib to the standard induction protocol had an additional beneficial effect. The speed and depth of the response to induction therapy, and the initial white blood cell count had an apparent effect on survival.

  12. Allelic Imbalances in Radiation—Associated Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Michael Rosemann

    2011-05-01

    Full Text Available Acute myeloid leukemia (AML can develop as a secondary malignancy following radiotherapy, but also following low-dose environmental or occupational radiation exposure. Therapy-related AML frequently carries deletions of chromosome 5q and/or 7, but for low-dose exposure associated AML this has not been described. For the present study we performed genome-wide screens for loss-of-heterozygosity (LOH in a set of 19 AML cases that developed after radiation-exposure following the Chernobyl accident. Using Affymetrix SNP arrays we found large regions of LOH in 16 of the cases. Eight cases (42% demonstrated LOH at 5q and/or 7, which is a known marker of complex karyotypic changes and poor prognosis. We could show here for the first time that exposure to low-dose ionizing radiation induces AML with molecular alterations similar to those seen in therapy-related cases.

  13. Biology and relevance of human acute myeloid leukemia stem cells.

    Science.gov (United States)

    Thomas, Daniel; Majeti, Ravindra

    2017-03-23

    Evidence of human acute myeloid leukemia stem cells (AML LSCs) was first reported nearly 2 decades ago through the identification of rare subpopulations of engrafting cells in xenotransplantation assays. These AML LSCs were shown to reside at the apex of a cellular hierarchy that initiates and maintains the disease, exhibiting properties of self-renewal, cell cycle quiescence, and chemoresistance. This cancer stem cell model offers an explanation for chemotherapy resistance and disease relapse and implies that approaches to treatment must eradicate LSCs for cure. More recently, a number of studies have both refined and expanded our understanding of LSCs and intrapatient heterogeneity in AML using improved xenotransplant models, genome-scale analyses, and experimental manipulation of primary patient cells. Here, we review these studies with a focus on the immunophenotype, biological properties, epigenetics, genetics, and clinical associations of human AML LSCs and discuss critical questions that need to be addressed in future research. © 2017 by The American Society of Hematology.

  14. Genetic Testing in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    Science.gov (United States)

    Nardi, Valentina; Hasserjian, Robert P

    2016-03-01

    Cytogenetic analysis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is essential for disease diagnosis, classification, prognostic stratification, and treatment guidance. Molecular genetic analysis of CEBPA, NPM1, and FLT3 is already standard of care in patients with AML, and mutations in several additional genes are assuming increasing importance. Mutational analysis of certain genes, such as SF3B1, is also becoming an important tool to distinguish subsets of MDS that have different biologic behaviors. It is still uncertain how to optimally combine karyotype with mutation data in diagnosis and risk-stratification of AML and MDS, particularly in cases with multiple mutations and/or several mutationally distinct subclones. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. [Diagnostics, classification and prognostic criteria of acute myeloid leukemia].

    Science.gov (United States)

    Heilmeier, Bernhard; Buske, Christian; Spiekermann, Karsten; Bohlander, Stefan; Feuring-Buske, Michaela; Hiddemann, Wolfgang; Braess, Jan

    2007-04-15

    The continuously growing knowledge about criteria important for biology, pathogenesis, prognosis and treatment of acute myeloid leukemia (AML) necessitates a broad spectrum of diagnostic methods for first diagnosis and for the further course of the disease. Relevant diagnostic techniques (cytomorphology with cytochemistry, immunophenotyping, cytogenetics and molecular genetics, DNA array) are described - with a focus on their mode of operation as well on their clinical significance. Due to the high clinical relevance and growing complexity, AML diagnostics should be performed in specialized laboratories. Compared to the FAB classification which is based primarily on morphological criteria, the classification recommended in 2001 by the WHO additionally takes cytogenetics, molecular genetics and further clinical factors into consideration. Both classifications are described. A wide range of prognostic criteria of AML is discussed on the basis of currently available clinical data. The most important criteria are the karyotype of the leukemic clone and the patient's age.

  16. Myeloperoxidase index and subtypes of acute myeloid leukemia.

    Science.gov (United States)

    Eivazi-Ziaei, Jamal

    2009-06-01

    Acute myeloid leukemia (AML) should be classified into subtypes according to the French-American-British (FAB) or, preferably, the newer World Health Organization (WHO) classification schemes. FAB is purely a morphological classification. It does not determine treatment (except M3) or prognosis for the patient which requires cytogenetics. Haematological analyzer had been used for classification of leukaemia in several studies. Neutrophil myeloperoxidase activity (MPXI) can be performed by Technicon H1 (Bayer) automated cell counter. The aim of this study was the statement of myeloperoxidase index and subgroups of AML. In the study of medical records of 72 patients with AML from 2006-7, we found that MPXI was negative in M4 and M5 while 75% of M3 cases had high MPXI values. MPXI level may help to differentiate subtypes of AML.

  17. Relapsing acute myeloid leukemia presenting as hypopyon uveitis

    Directory of Open Access Journals (Sweden)

    Sapna P Hegde

    2011-01-01

    Full Text Available Anterior segment infiltration in acute myeloid leukemia (AML presenting as hypopyon uveitis is very rare. We report this case as an uncommon presentation in a patient on remission after bone marrow transplant for AML. In addition to the hypopyon, the patient presented with "red eye" caused by ocular surface disease due to concurrent graft-versus-host disease and glaucoma. The classical manifestations of masquerade syndrome due to AML were altered by concurrent pathologies. Media opacities further confounded the differential diagnosis. We highlight the investigations used to arrive at a definitive diagnosis. In uveitis, there is a need to maintain a high index of clinical suspicion, as early diagnosis in ocular malignancy can save sight and life.

  18. Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia.

    Science.gov (United States)

    Rydström, Anna; Hallner, Alexander; Aurelius, Johan; Sander, Frida Ewald; Bernson, Elin; Kiffin, Roberta; Thoren, Fredrik Bergh; Hellstrand, Kristoffer; Martner, Anna

    2017-08-01

    Relapse of leukemia in the postchemotherapy phase contributes to the poor prognosis and survival in patients with acute myeloid leukemia (AML). In an international phase IV trial (ClinicalTrials.gov; NCT01347996), 84 patients with AML in first complete remission who had not undergone transplantation received immunotherapy with histamine dihydrochloride (HDC) and low-dose IL-2 with the aim of preventing relapse. The dynamics of myeloid cell counts and expression of activation markers was assessed before and after cycles of immunotherapy and correlated with clinical outcome in terms of relapse risk and survival. During cycles, a pronounced increase in blood eosinophil counts was observed along with a reduction in monocyte and neutrophil counts. A strong reduction of blood monocyte counts during the first HDC/IL-2 treatment cycle predicted leukemia-free survival. The HDC component of the immunotherapy exerts agonist activity at histamine type 2 receptors (H2Rs) that are expressed by myeloid cells. It was observed that the density of H 2 R expression in blood monocytes increased during cycles of immunotherapy and that high monocyte H 2 R expression implied reduced relapse risk and improved overall survival. Several other activation markers, including HLA-DR, CD86, and CD40, were induced in monocytes and dendritic cells during immunotherapy but did not predict clinical outcome. In addition, expression of HLA-ABC increased in all myeloid populations during therapy. A low expression of HLA-ABC was associated with reduced relapse risk. These results suggest that aspects of myeloid cell biology may impact clinical benefit of relapse-preventive immunotherapy in AML. © Society for Leukocyte Biology.

  19. [Acute myeloid leukemia. Genetic diagnostics and molecular therapy].

    Science.gov (United States)

    Schlenk, R F; Döhner, K; Döhner, H

    2013-02-01

    Acute myeloid leukemia (AML) is a genetically heterogeneous disease. The genetic diagnostics have become an essential component in the initial work-up for disease classification, prognostication and prediction. More and more promising molecular targeted therapeutics are becoming available. A prerequisite for individualized treatment strategies is a fast pretherapeutic molecular screening including the fusion genes PML-RARA, RUNX1-RUNX1T1 and CBFB-MYH11 as well as mutations in the genes NPM1, FLT3 and CEBPA. Promising new therapeutic approaches include the combination of all- trans retinoic acid and arsentrioxid in acute promyelocytic leukemia, the combination of intensive chemotherapy with KIT inhibitors in core-binding factor AML and FLT3 inhibitors in AML with FLT3 mutation, as well as gemtuzumab ozogamicin therapy in patients with low and intermediate cytogenetic risk profiles. With the advent of the next generation sequencing technologies it is expected that new therapeutic targets will be identified. These insights will lead to a further individualization of AML therapy.

  20. Azelaic Acid Exerts Antileukemic Activity in Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Yunbao Pan

    2017-06-01

    Full Text Available Acute myeloid leukemia (AML is an acute leukemia common in most adults; its prevalence intensifies with age. The overall survival of AML is very poor because of therapeutic resistance. Azelaic acid (AZA is non-toxic, non-teratogenic, and non-mutagenic and its antitumor effect on various tumor cells is well established; Nonetheless, its therapeutic effects in AML cells are largely unknown. In this study, it was shown that AZA significantly inhibits the cell viability and induces apoptosis in AML cells in a dose-dependent manner. Additionally, AZA suppressed the expression of phosphorylated Akt, Jab1 and Trx, and this suppression was enhanced by treatment with Jab1 siRNA. Furthermore, AZA sensitized AML cells to Ara-c chemotherapy. The suppressive effect of AZA on tumor growth was examined in vivo by subcutaneously inoculated AML cells in a tumor model using nude mice. These findings indicate that AZA is useful as an effective ingredient in antineoplastic activity.

  1. Evolving Therapies in Acute Myeloid Leukemia: Progress at Last?

    Science.gov (United States)

    DeAngelo, Daniel J; Stein, Eytan M; Ravandi, Farhad

    2016-01-01

    Acute myeloid leukemia (AML) is an acquired disease characterized by chromosomal translocations and somatic mutations that lead to leukemogenesis. Systemic combination chemotherapy with an anthracycline and cytarabine remains the standard induction regimen for "fit" adults. Patients who achieve complete remission generally receive postinduction therapy with cytarabine-based chemotherapy or an allogeneic bone marrow transplant. Those unfit for induction chemotherapy are treated with hypomethylating agents (HMAs), low-dose cytarabine, or they are offered supportive care alone with transfusions and prophylactic antimicrobials. The revolution in understanding the genetics of AML, facilitated by next-generation sequencing, has led to many new drugs against driver mutations. Better methods of identification of leukemic blasts have provided us with better means to detect the disease left behind after cytotoxic chemotherapy regimens. This measurable residual disease has been correlated with poorer relapse-free survival, demonstrating the need for novel strategies to eradicate it to improve the outcome of patients with acute leukemias. In this article, we discuss adapting and improving AML therapy by age and comorbidities, emerging targeted therapies in AML, and minimal residual disease (MRD) assessment in AML.

  2. Acute Myeloid Leukemia: Clinical Spectrum of 125 Patients.

    Science.gov (United States)

    Sultan, Sadia; Zaheer, Hasan Abbas; Irfan, Syed Mohammed; Ashar, Sana

    2016-01-01

    Acute myeloid leukemia is an acquired clonal heterogeneous stem cell disorder. Hence, various parameters are sought out to categorize this disease into subtypes, so that as a consequence specific treatment modalities can be offered. Conventionally, the practically used method for classification utilizes French American British (FAB) criteria based on morphology and cytochemistry. The aim of present study was to determine the current spectrum of AML sub types in patients in Karachi. This single centre cross sectional study was conducted at Liaquat National Hospital, Karachi, extending from January 2010 to December 2014. Data were retrieved from archives were analyzed with SPSS version 22. A total of 125 patients were diagnosed at our institution with de novo AML during five years period, 76 males and 49 females. Median age was 34.5 years. AML-M1 was the predominant FAB subtype (23.2%) followed by M2 (18.4%), M3 and M4 (16% each), M0 (14.4%), M5 (7.2%), M6 (3.2%) and M7 (1.6%). AML in Pakistani patients is seen in a relatively young population. The most common FAB subtype observed in our study was acute myeloblastic leukemia, without maturation (M1).

  3. DNA copy number analysis from mice with radiation-induced acute myeloid leukemia

    Data.gov (United States)

    National Aeronautics and Space Administration — Certain mouse strains such as CBA C3H and RFM have high incidence of radiation-induced acute myeloid leukemia (AML). The data in this series wer generated by using...

  4. Clinical impact of leukemic blast heterogeneity at diagnosis in cytogenetic intermediate-risk acute myeloid leukemia

    DEFF Research Database (Denmark)

    Hoffmann, Marianne Hutchings; Klausen, Tobias Wirenfeldt; Boegsted, Martin

    2012-01-01

    Individual cellular heterogeneity within the acute myeloid leukemia (AML) bone marrow samples can be observed by multi parametric flow cytometry analysis (MFC) indicating that immunophenotypic screening for leukemic blast subsets may have prognostic impact....

  5. Outcome of pediatric acute myeloid leukemia patients receiving intensive care in the United States.

    Science.gov (United States)

    Maude, Shannon L; Fitzgerald, Julie C; Fisher, Brian T; Li, Yimei; Huang, Yuan-Shung; Torp, Kari; Seif, Alix E; Kavcic, Marko; Walker, Dana M; Leckerman, Kateri H; Kilbaugh, Todd J; Rheingold, Susan R; Sung, Lillian; Zaoutis, Theoklis E; Berg, Robert A; Nadkarni, Vinay M; Thomas, Neal J; Aplenc, Richard

    2014-02-01

    Children with acute myeloid leukemia are at risk for sepsis and organ failure. Outcomes associated with intensive care support have not been studied in a large pediatric acute myeloid leukemia population. Our objective was to determine hospital mortality of pediatric acute myeloid leukemia patients requiring intensive care. Retrospective cohort study of children hospitalized between 1999 and 2010. Use of intensive care was defined by utilization of specific procedures and resources. The primary endpoint was hospital mortality. Forty-three children's hospitals contributing data to the Pediatric Health Information System database. Patients who are newly diagnosed with acute myeloid leukemia and who are 28 days through 18 years old (n = 1,673) hospitalized any time from initial diagnosis through 9 months following diagnosis or until stem cell transplant. A reference cohort of all nononcology pediatric admissions using the same intensive care resources in the same time period (n = 242,192 admissions) was also studied. None. One-third of pediatric patients with acute myeloid leukemia (553 of 1,673) required intensive care during a hospitalization within 9 months of diagnosis. Among intensive care admissions, mortality was higher in the acute myeloid leukemia cohort compared with the nononcology cohort (18.6% vs 6.5%; odds ratio, 3.23; 95% CI, 2.64-3.94). However, when sepsis was present, mortality was not significantly different between cohorts (21.9% vs 19.5%; odds ratio, 1.17; 95% CI, 0.89-1.53). Mortality was consistently higher for each type of organ failure in the acute myeloid leukemia cohort versus the nononcology cohort; however, mortality did not exceed 40% unless there were four or more organ failures in the admission. Mortality for admissions requiring intensive care decreased over time for both cohorts (23.7% in 1999-2003 vs 16.4% in 2004-2010 in the acute myeloid leukemia cohort, p = 0.0367; and 7.5% in 1999-2003 vs 6.5% in 2004-2010 in the nononcology

  6. Current diagnosis and treatment for pediatric acute myeloid leukemia.

    Science.gov (United States)

    Shiba, Norio

    2017-01-01

    Acute myeloid leukemia (AML) is a complex disease caused by chromosomal aberrations, mutations, epigenetic modifications, and the deregulated expression of genes, leading to increased myeloid cell proliferation and decreased hematopoietic progenitor cell differentiation. Although most of these aberrations are correlated with prognosis, accurate risk stratification remains a challenge even after incorporating these molecular markers. Currently, some genetic mutations that allow risk stratification have been identified in adult AML, including DNMT3A and IDH1/2. However, these mutations are rare in pediatric AML cases, indicating that a different pathogenesis may exist between adult and pediatric AML. To reveal further details of pediatric AML pathogenesis, the authors performed whole-exome sequencing and whole-transcriptome analysis using massively parallel sequencing technologies in addition to gene expression array. We found that PRDM16 and EVI1-overexpressing patients had significantly worse overall survival and event-free survival, and these overexpressed genes were useful for stratifying patients with FLT3-ITD positive and/or normal karyotype. In order to further this work and establish more appropriate risk classification and molecular target drug development, target validation clinical studies are needed and expected.

  7. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.

    Science.gov (United States)

    Lindsley, R Coleman; Mar, Brenton G; Mazzola, Emanuele; Grauman, Peter V; Shareef, Sarah; Allen, Steven L; Pigneux, Arnaud; Wetzler, Meir; Stuart, Robert K; Erba, Harry P; Damon, Lloyd E; Powell, Bayard L; Lindeman, Neal; Steensma, David P; Wadleigh, Martha; DeAngelo, Daniel J; Neuberg, Donna; Stone, Richard M; Ebert, Benjamin L

    2015-02-26

    Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637. © 2015 by The American Society of Hematology.

  8. Multiplex fusion gene testing in pediatric acute myeloid leukemia.

    Science.gov (United States)

    Iijima-Yamashita, Yuka; Matsuo, Hidemasa; Yamada, Miho; Deguchi, Takao; Kiyokawa, Nobutaka; Shimada, Akira; Tawa, Akio; Takahashi, Hiroyuki; Tomizawa, Daisuke; Taga, Takashi; Kinoshita, Akitoshi; Adachi, Souichi; Horibe, Keizo

    2018-01-01

    Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required. A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation. Multiplex quantitative RT-PCR was performed to detect eight important fusion genes: AML1(RUNX1)-ETO(RUNX1T1), CBFB-MYH11, MLL(KMT2A)-AF9(MLLT3), MLL-ELL, MLL-AF6(MLLT4), FUS(TLS)-ERG, NUP98-HOXA9, and PML-RARA. Fusion genes were detected in 207 (46.2%) of the 448 AML-05 patient samples. After exclusion of two samples with PML-RARA, no chromosomal abnormalities were identified on karyotyping in 19 of 205 patients (9.3%) positive for fusion genes on RT-PCR. Fusion genes were confirmed on fluorescence in situ hybridization (FISH) in 11 of these 19 patients. In contrast, fusion genes were detected in 37 of 39 patients (94.9%) from the AML-P05 study, and 33 of these results were consistent with the karyotyping. There were discrepancies in four patients (10.8%), three with normal karyotypes and one in whom karyotyping was not possible. All four of these patients were PML-RARA positive on FISH. Multiplex quantitative RT-PCR-based fusion gene screening may be effective for diagnosis of pediatric AML. © 2017 Japan Pediatric Society.

  9. Direct and indirect targeting of MYC to treat acute myeloid leukemia

    OpenAIRE

    Kogan, Scott; Goga, Andrei; Brondfield, S; Brondfield, S; Umesh, S; Umesh, S; Corella, A; Corella, A; Zuber, J; Rappaport, AR; Rappaport, AR; Gaillard, C

    2015-01-01

    © 2015 The Author(s) Purpose: Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is often resistant to conventional therapies. The MYC oncogene is commonly overexpressed in AML but has remained an elusive target. We aimed to exami

  10. Diagnosis of acute myeloid leukemia in a dental hospital; report of a ...

    African Journals Online (AJOL)

    Acute myeloid leukemias (AMLs) are aggressive hematopoietic neoplasms that, if untreated, can lead to death within days. Owing to its high morbidity rate, early diagnosis and appropriate medical therapy is essential. Oral lesions may be the presenting feature of acute leukemias and are, therefore, important diagnostic ...

  11. Molecular Therapeutic Approaches for Pediatric Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Sarah K Tasian

    2014-03-01

    Full Text Available Approximately two thirds of children with acute myeloid leukemia (AML are cured with intensive multi-agent chemotherapy. However, primary chemorefractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic agents is not feasible given the potential for significant toxicity to normal tissues with conventional chemotherapy and the risk for long-term end-organ dysfunction. Significant emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with the goal of improving remission induction and minimizing relapse. Several promising agents are currently in clinical testing or late preclinical development for AML, including monoclonal antibodies against leukemia cell surface proteins, kinase inhibitors, proteasome inhibitors, epigenetic agents, and chimeric antigen receptor engineered T cell immunotherapies. Many of these therapies have been specifically tested in children with relapsed/refractory AML via phase 1 and 2 trials with a smaller number of new agents under phase 3 evaluation for children with de novo AML. Although successful identification and implementation of new drugs for children with AML remains a formidable challenge, enthusiasm for novel molecular therapeutic approaches is great given the potential for significant clinical benefit for children who will otherwise fail standard therapy.

  12. Karyotype complexity and prognosis in acute myeloid leukemia.

    Science.gov (United States)

    Stölzel, F; Mohr, B; Kramer, M; Oelschlägel, U; Bochtler, T; Berdel, W E; Kaufmann, M; Baldus, C D; Schäfer-Eckart, K; Stuhlmann, R; Einsele, H; Krause, S W; Serve, H; Hänel, M; Herbst, R; Neubauer, A; Sohlbach, K; Mayer, J; Middeke, J M; Platzbecker, U; Schaich, M; Krämer, A; Röllig, C; Schetelig, J; Bornhäuser, M; Ehninger, G

    2016-01-15

    A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with ⩾4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.

  13. Recent developments in immunotherapy of acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Felix S. Lichtenegger

    2017-07-01

    Full Text Available Abstract The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years. Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1 antibody-drug conjugates, (2 T cell-recruiting antibody constructs, (3 chimeric antigen receptor (CAR T cells, (4 checkpoint inhibitors, and (5 dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results. While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts.

  14. Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells.

    Science.gov (United States)

    Petrov, Ivan; Suntsova, Maria; Mutorova, Olga; Sorokin, Maxim; Garazha, Andrew; Ilnitskaya, Elena; Spirin, Pavel; Larin, Sergey; Kovalchuk, Olga; Prassolov, Vladimir; Zhavoronkov, Alex; Roumiantsev, Alexander; Buzdin, Anton

    2016-11-19

    Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.

  15. Cutaneous myeloid sarcoma associated with chronic myeloid leukemia*

    OpenAIRE

    Vasconcelos, Erica Rodrigues de Araujo; Bauk, Alexander Richard; Rochael, Mayra Carrijo

    2017-01-01

    Abstract: Myeloid sarcoma is an extramedullary tumor of malignant myeloid cells often associated with acute myeloid leukemia, chronic myeloproliferative disorders and myelodysplastic syndromes. The skin is one of the most commonly affected sites. We report a rare case of cutaneous myeloid sarcoma associated with chronic myeloid leukemia.

  16. High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia

    Science.gov (United States)

    2018-02-28

    Acute Leukemia of Ambiguous Lineage; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  17. Leukemia Associated Antigens: Their Dual Role as Biomarkers and Immunotherapeutic Targets for Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Michael Schmitt

    2007-01-01

    Full Text Available Leukemia associated antigens (LAAs are being increasingly identified by methods such as cytotoxic T-lymphocyte (CTL cloning, serological analysis of recombinant cDNA expression libraries (SEREX and mass spectrometry (MS. In additional, large scale screening techniques such as microarray, single nucleotide polymorphisms (SNPs, serial analysis of gene expression (SAGE and 2-dimensional gel electrophoresis (2-DE have expanded our understanding of the role that tumor antigens play in the biological processes which are perturbed in acute myeloid leukemia (AML. It has become increasingly apparent that these antigens play a dual role, not only as targets for immunotherapy, but also as biomarkers of disease state, stage, response to treatment and survival. We need biomarkers to enable the identification of the patients who are most likely to benefit from specific treatments (conventional and/or novel and to help clinicians and scientists improve clinical end points and treatment design. Here we describe the LAAs identified in AML, to date, which have already been shown to play a dual role as biomarkers of AML disease.Abbreviations: AML: acute myeloid leukemia; APL: acute promyelocytic leukemia; ATRA: all-trans-retinoic acid; B-CLL: B-cell chronic lymphocytic leukemia; CT: cancer-testis; CTL: cytotoxic T-lymphocyte; FAB: French-American-British; HI: hypusination inhibitors; HSP: heat shock protein; ITD: internal tandem duplication; LAA: leukemia associated antigen; MDS: myelodysplastic syndrome; MGEA6: meningioma antigen 6; MPD: myeloproliferative disease; MS: mass spectrometry; NK: natural killer; PRAME: preferentially expressed antigen of melanoma; PRTN3: proteinase 3; RAGE-1: renal antigen 1; RHAMM: receptor for hyaluronic acid-mediated motility; RQ-PCR: real-time PCR; SAGE: serial analysis of gene expression; SCT: stem cell transplant; SEREX: serological analysis of recombinant cDNA expression libraries; SNPs: single nucleotide polymorphisms; UPD

  18. In vivo RNAi screening for the identification of oncogenes and tumor suppressors in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Ge, Ying

    Acute myeloid leukemia (AML) is an aggressive malignancy characterized by uncontrolled expansion of immature myeloid cells in the hematopoietic tissues. Alternative splicing and epigenetic regulation are two mechanisms implicated in the pathogenesis of AML. In order to identify the essential spli...

  19. Acquired mutations in ASXL1 in acute myeloid leukemia: Prevalence and prognostic value

    NARCIS (Netherlands)

    M. Pratcorona (Marta); S. Abbas (Saman); M.A. Sanders (Mathijs); J.E. Koenders (Jasper); F.G. Kavelaars (François); C.A.J. Erpelinck-Verschueren (C. A J); A. Zeilemakers (Annelieke); B. Löwenberg (Bob); P.J.M. Valk (Peter)

    2012-01-01

    textabstractSomatic mutations in the additional sex comb-like 1 (ASXL1) gene have been described in various types of myeloid malignancies, including acute myeloid leukemia. Analysis of novel markers, such as ASXL1 mutations, in independent clinical trials is indispensable before considering them for

  20. Absence of mutations in the RET gene in acute myeloid leukemia

    NARCIS (Netherlands)

    Visser, M; Hofstra, RMW; Stulp, RP; Wu, Y; Buys, CHCM; Willemze, R; Landegent, JE

    Expression of the tyrosine kinase receptor RET has previously been detected in normal hematopoietic cells, and especially in cells of the myeloid lineage. Furthermore, RET was shown to be differentially expressed in acute myeloid leukemia (AML), a disease characterized by excessive cell growth and

  1. Expression of CD71 by flow cytometry in acute leukemias: More often seen in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Amit Pande

    2016-01-01

    Full Text Available Background: CD71 is a marker that has been usually used for identifying dysplasia in the erythroid series. We have tried to evaluate the expression of CD71 in various types of acute leukemias. Materials and Methods: We studied 48 patients of acute leukemia, of which 25 were acute myeloid leukemia (AML, 13 were precursor B-acute lymphoblastic leukemia (B-ALL, 8 were T-ALL, and 2 were mixed phenotype acute leukemia (T/myeloid as per the WHO classification. Results: We found that the expression of CD71 was most prevalent in AMLs (84%, followed by T-ALL (50% and least in B-ALL (30%. Conclusion: This finding clearly shows the higher expression of CD71 in AMLs compared to other common type of leukemias, such as B- and T-ALL. We suggest that the high expression of CD71 in AMLs could be used as a diagnostic marker and may also be used for minimal residual disease analysis after further studies in posttreatment scenario. This study is the first of its kind in the South Asian population.

  2. Expression of CD71 by flow cytometry in acute leukemias: More often seen in acute myeloid leukemia.

    Science.gov (United States)

    Pande, Amit; Dorwal, Pranav; Jain, Dharmendra; Tyagi, Neetu; Mehra, Simmi; Sachdev, Ritesh; Raina, Vimarsh

    2016-01-01

    CD71 is a marker that has been usually used for identifying dysplasia in the erythroid series. We have tried to evaluate the expression of CD71 in various types of acute leukemias. We studied 48 patients of acute leukemia, of which 25 were acute myeloid leukemia (AML), 13 were precursor B-acute lymphoblastic leukemia (B-ALL), 8 were T-ALL, and 2 were mixed phenotype acute leukemia (T/myeloid) as per the WHO classification. We found that the expression of CD71 was most prevalent in AMLs (84%), followed by T-ALL (50%) and least in B-ALL (30%). This finding clearly shows the higher expression of CD71 in AMLs compared to other common type of leukemias, such as B- and T-ALL. We suggest that the high expression of CD71 in AMLs could be used as a diagnostic marker and may also be used for minimal residual disease analysis after further studies in posttreatment scenario. This study is the first of its kind in the South Asian population.

  3. Base excision repair deficiency in acute myeloid leukemia

    International Nuclear Information System (INIS)

    Scheer, N.M.

    2009-01-01

    Acute myeloid leukemia (AML) is an aggressive malignancy of the hematopoietic system arising from a transformed myeloid progenitor cell. Genomic instability is the hallmark of AML and characterized by a variety of cytogenetic and molecular abnormalities. Whereas 10% to 20% of AML cases reflect long-term sequelae of cytotoxic therapies for a primary disorder, the etiology for the majority of AMLs remains unknown. The integrity of DNA is under continuous attack from a variety of exogenous and endogenous DNA damaging agents. The majority of DNA damage is caused by constantly generated reactive oxygen species (ROS) resulting from metabolic by-products. Base excision repair (BER) is the major DNA repair mechanism dealing with DNA base lesions that are induced by oxidative stress or alkylation. In this study we investigated the BER in AML. Primary AML patients samples as well as AML cell lines were treated with hydrogen peroxide (H 2 O 2 ). DNA damage induction and repair was monitored by the alkaline comet assay. In 15/30 leukemic samples from patients with therapy-related AML, in 13/35 with de novo AML and 14/26 with AML following a myelodysplastic syndrome, significantly reduced single strand breaks (SSBs) representing BER intermediates were found. In contrast, normal SSB formation was seen in mononuclear cells of 30 healthy individuals and 30/31 purified hematopoietic stem- and progenitor cell preparations obtained from umbilical cord blood. Additionally, in 5/10 analyzed AML cell lines, no SSBs were formed upon H 2 O 2 treatment, either. Differences in intracellular ROS concentrations or apoptosis could be excluded as reason for this phenomenon. A significantly diminished cleavage capacity for 7,8-dihydro-8-oxoguanine as well as for Furan was observed in cell lines that exhibited no SSB formation. These data demonstrate for the first time that initial steps of BER are impaired in a proportion of AML cell lines and leukemic cells from patients with different forms of

  4. Drug Repurposing for the Treatment of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Vibeke Andresen

    2017-11-01

    Full Text Available Acute myeloid leukemia (AML is a heterogeneous disease characterized by the accumulation of immature myeloid progenitor cells in the bone marrow, compromising of normal blood cell production and ultimately resulting in bone marrow failure. With a 20% overall survival rate at 5 years and 50% in the 18- to 65-year-old age group, new medicines are needed. It is proposed that development of repurposed drugs may be a part of the new therapy needed. AML is subdivided into recurrent molecular entities based on molecular genetics increasingly accessible for precision medicine. Novel therapy developments form a basis for novel multimodality therapy and include liposomal daunorubicin/cytarabine, broad or FLT3-specific tyrosine kinase inhibitors, Bcl-2 family inhibitors, selective inhibitors of nuclear export, metabolic inhibitors, and demethylating agents. The use of non-transplant immunotherapy is in early development in AML with the exceptional re-approval of a toxin-conjugated anti-CD33. However, the full potential of small molecule inhibitors and modalities like immunological checkpoint inhibitors, immunostimulatory small molecules, and CAR-T cell therapy is unknown. Some novel therapeutics will certainly benefit AML patient subgroups; however, due to high cost, more affordable alternatives are needed globally. Also the heterogeneity of AML will likely demand a broader repertoire of therapeutic molecules. Drug repurposing or repositioning represent a source for potential therapeutics with well-known toxicity profiles and reasonable prices. This implies that biomarkers of response need to accompany the development of antileukemic therapies for sharply defined patient subgroups. We will illustrate repurposing in AML with selected examples and discuss some experimental and regulatory limitations that may obstruct this development.

  5. A comparison of surface marker analysis and FAB classification in acute myeloid leukemia

    NARCIS (Netherlands)

    van der Reijden, H. J.; van Rhenen, D. J.; Lansdorp, P. M.; van't Veer, M. B.; Langenhuijsen, M. M.; Engelfriet, C. P.; von dem Borne, A. E.

    1983-01-01

    Surface marker analysis with rosette tests and a large panel of xenoantisera and monoclonal antibodies was done on the malignant cells of 55 patients with acute myeloid leukemia (AML). The diagnosis was made on morphological and cytochemical grounds, and the leukemias were classified according to

  6. Maxillo-orbital granulocytic sarcoma in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Chandana Chakraborti

    2016-01-01

    Full Text Available Granulocytic sarcoma or chloroma, a manifestation of acute myeloid leukemia (AML is a rare cause of childhood proptosis. A 14-year-old boy presented with progressively increasing unilateral proptosis and swelling of lower eyelid and face on the right side. Contrast enhanced computed tomographic images revealed enhancing infiltrates occupying the right orbit, maxillary antrum, and infratemporal fossa. Incisional biopsy from the orbital swelling and the bone marrow aspirate showing leukemic blast cells confirmed the diagnosis of AML. The peripheral smear was normal initially, but high total leukocytic count with immature blast cells was evident after 1-month of presentation. Chemotherapy brought about the remission of the disease. However, the delay in diagnosis because of negative peripheral blood smear examination and inconclusive fine-needle aspiration biopsy led to the loss of vision in right eye. Diagnosis of such case can be made by a combination of good clinical examination and relevant investigations. This case of maxillo-orbital granulocytic sarcoma is reported because of its rarity and to emphasize the clinical and cyto-histological features and problems concerning differential diagnosis.

  7. [Acute myeloid leukemia originating from the same leukemia clone after the complete remission of acute lymphoid leukemia].

    Science.gov (United States)

    Matsuda, Isao; Nakamaki, Tsuyoshi; Amaya, Hiroshi; Kiyosaki, Masanobu; Kawakami, Keiichiro; Yamada, Kazunari; Yokoyama, Akihiro; Hino, Ken-ichiro; Tomoyasu, Shigeru

    2003-09-01

    A 22-year-old female was diagnosed as having acute lymphoid leukemia (ALL) in February 1995, from the findings of peroxidase negative, CD10+, CD19+, TdT+ and rearrangement of IgH and TCR beta. AdVP (doxorubicin, vincristine and prednisolone) therapy achieved a complete remission (CR). Bone marrow transplantation had to be abandoned because of the lack of an HLA-identical donor. Intensification therapy was thus carried out repeatedly. In June 1998, myeloblast with Auer rods, peroxidase positive, CD13+, CD33+ and HLA-DR+, appeared. The patient was diagnosed as having lineage switch acute myeloid leukemia (AML) from ALL. Though A-DMP (cytosine arabinoside, daunorubicin, 6-mercaptopurine) therapy was resistant, AdVP therapy led to a CR. The patient died of cardiotoxicity from anthracyclines in February 1999. From the results of the Ramasamy method using the clonal rearrangements of the Ig heavy chain gene locus, the origin of the pathological cells of ALL and AML was indicated to be the same leukemia clone.

  8. Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

    International Nuclear Information System (INIS)

    Eriksson, A; Österroos, A; Hassan, S; Gullbo, J; Rickardson, L; Jarvius, M; Nygren, P; Fryknäs, M; Höglund, M; Larsson, R

    2015-01-01

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC 1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis

  9. Potential of ponatinib to treat chronic myeloid leukemia and acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Price KE

    2013-08-01

    Full Text Available Kimberly E Price, Najma Saleem, Georgina Lee, Michael SteinbergMassachusetts College of Pharmacy and Health Sciences University, Worcester, MA, USAAbstract: Development of BCR-ABL tyrosine kinase inhibitors (TKIs have improved outcomes for patients diagnosed with chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. However, resistance or intolerance to these TKIs still leaves some patients without many treatment options. One point mutation in particular, the T315I mutation, has been shown to be resistant to first and second generation TKIs. The third generation TKI, ponatinib, may provide an option for these patients. Ponatinib (Iclusig®, an orally available, pan-tyrosine kinase inhibitor has a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. A Phase II study evaluated ponatinib in patients who were resistant or intolerant to nilotinib or dasatinib or patients who had the T315I mutation. In the Phase II study, ponatinib produced a major cytogenetic response in 54% of chronic phase chronic myeloid leukemia patients. It further achieved major hematologic response in 52% of patients in the accelerated phase, 31% of patients in the blast phase, and 41% of Philadelphia chromosome positive acute lymphoblastic leukemia patients. Ponatinib also showed efficacy in patients with the T315I mutation. Serious adverse events included arterial thrombosis, hepatotoxicity, cardiovascular risks, pancreatitis, hemorrhage, fluid retention, myelosuppression, rash, abdominal pain, and embryo–fetal toxicity. Due to the risk of these adverse events and potential drug interactions, the use of ponatinib must be carefully weighed against the benefits in treating patients who have limited treatment options.Keywords: BCR-ABL, tyrosine kinase inhibitor, TKI, T315I, Philadelphia chromosome

  10. Treatment of Acute Myeloid Leukemia in Adolescent and Young Adult Patients

    Directory of Open Access Journals (Sweden)

    Guldane Cengiz Seval

    2015-03-01

    Full Text Available The objectives of this review were to discuss standard and investigational treatment strategies for adolescent and young adult with acute myeloid leukemia, excluding acute promyelocytic leukemia. Acute myeloid leukemia (AML in adolescent and young adult patients (AYAs may need a different type of therapy than those currently used in children and older patients. As soon as AML is diagnosed, AYA patient should be offered to participate in well-designed clinical trials. The standard treatment approach for AYAs with AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or stem cell transplantation, depending on the ability of the patient to tolerate intensive treatment and cytogenetic features. Presently, continuing progress of novel drugs targeting specific pathways in acute leukemia may bring AML treatment into a new era.

  11. C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia

    NARCIS (Netherlands)

    Bakker, Alexander B. H.; van den Oudenrijn, Sonja; Bakker, Arjen Q.; Feller, Nicole; van Meijer, Marja; Bia, Judith A.; Jongeneelen, Mandy A. C.; Visser, Therese J.; Bijl, Nora; Geuijen, Cecilia A. W.; Marissen, Wilfred E.; Radosevic, Katarina; Throsby, Mark; Schuurhuis, Gerrit Jan; Ossenkoppele, Gert J.; de Kruif, John; Goudsmit, Jaap; Kruisbeek, Ada M.

    2004-01-01

    Acute myeloid leukemia (AML) has a poor prognosis due to treatment-resistant relapses. A humanized anti-CD33 antibody (Mylotarg) showed a limited response rate in relapsed AML. To discover novel AML antibody targets, we selected a panel of single chain Fv fragments using phage display technology

  12. Genomic Classification and Prognosis in Acute Myeloid Leukemia.

    Science.gov (United States)

    Papaemmanuil, Elli; Gerstung, Moritz; Bullinger, Lars; Gaidzik, Verena I; Paschka, Peter; Roberts, Nicola D; Potter, Nicola E; Heuser, Michael; Thol, Felicitas; Bolli, Niccolo; Gundem, Gunes; Van Loo, Peter; Martincorena, Inigo; Ganly, Peter; Mudie, Laura; McLaren, Stuart; O'Meara, Sarah; Raine, Keiran; Jones, David R; Teague, Jon W; Butler, Adam P; Greaves, Mel F; Ganser, Arnold; Döhner, Konstanze; Schlenk, Richard F; Döhner, Hartmut; Campbell, Peter J

    2016-06-09

    Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes. We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2(R172) mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials. The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT

  13. Acute Myeloid Leukemia: analysis of epidemiological profile and survival rate.

    Science.gov (United States)

    de Lima, Mariana Cardoso; da Silva, Denise Bousfield; Freund, Ana Paula Ferreira; Dacoregio, Juliana Shmitz; Costa, Tatiana El Jaick Bonifácio; Costa, Imaruí; Faraco, Daniel; Silva, Maurício Laerte

    2016-01-01

    To describe the epidemiological profile and the survival rate of patients with acute myeloid leukemia (AML) in a state reference pediatric hospital. Clinical-epidemiological, observational, retrospective, descriptive study. The study included new cases of patients with AML, diagnosed between 2004 and 2012, younger than 15 years. Of the 51 patients studied, 84% were white; 45% were females and 55%, males. Regarding age, 8% were younger than 1 year, 47% were aged between 1 and 10 years, and 45% were older than 10 years. The main signs/symptoms were fever (41.1%), asthenia/lack of appetite (35.2%), and hemorrhagic manifestations (27.4%). The most affected extra-medullary site was the central nervous system (14%). In 47% of patients, the white blood cell (WBC) count was below 10,000/mm(3) at diagnosis. The minimal residual disease (MRD) was less than 0.1%, on the 15th day of treatment in 16% of the sample. Medullary relapse occurred in 14% of cases. When comparing the bone marrow MRD with the vital status, it was observed that 71.42% of the patients with type M3 AML were alive, as were 54.05% of those with non-M3 AML. The death rate was 43% and the main proximate cause was septic shock (63.6%). In this study, the majority of patients were male, white, and older than 1 year. Most patients with WBC count <10,000/mm(3) at diagnosis lived. Overall survival was higher in patients with MRD <0.1%. The prognosis was better in patients with AML-M3. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  14. Rhabdomyolysis Following Initiation of Posaconazole Use for Antifungal Prophylaxis in a Patient With Relapsed Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Mayur D. Mody MD

    2017-02-01

    Full Text Available Posaconazole is a commonly used medication for antifungal prophylaxis in patients with high-risk acute leukemia, such as acute myeloid leukemia. Despite clinical data that show that posaconazole is superior to other antifungal prophylaxis medications, posaconazole is known to have many side effects and drug-drug interactions. We present a patient who developed rhabdomyolysis after being started on posaconazole for prophylaxis in the setting of relapsed acute myeloid leukemia.

  15. Rhabdomyolysis Following Initiation of Posaconazole Use for Antifungal Prophylaxis in a Patient With Relapsed Acute Myeloid Leukemia

    Science.gov (United States)

    Mody, Mayur D.; Ravindranathan, Deepak; Gill, Harpaul S.; Kota, Vamsi K.

    2017-01-01

    Posaconazole is a commonly used medication for antifungal prophylaxis in patients with high-risk acute leukemia, such as acute myeloid leukemia. Despite clinical data that show that posaconazole is superior to other antifungal prophylaxis medications, posaconazole is known to have many side effects and drug-drug interactions. We present a patient who developed rhabdomyolysis after being started on posaconazole for prophylaxis in the setting of relapsed acute myeloid leukemia. PMID:28203579

  16. Pubertal development and fertility in survivors of childhood acute myeloid leukemia treated with chemotherapy only

    DEFF Research Database (Denmark)

    Molgaard-Hansen, Lene; Skou, Anne-Sofie; Juul, Anders

    2013-01-01

    More than 60% of children with acute myeloid leukemia (AML) become long-term survivors. Most are cured using chemotherapy without hematopoietic stem cell transplantation (HSCT). We report on pubertal development and compare self-reported parenthood among AML survivors and their siblings.......More than 60% of children with acute myeloid leukemia (AML) become long-term survivors. Most are cured using chemotherapy without hematopoietic stem cell transplantation (HSCT). We report on pubertal development and compare self-reported parenthood among AML survivors and their siblings....

  17. Molecular and cytogenetic abnormalities in acute myeloid leukemia: review and case studies

    OpenAIRE

    Velloso,Elvira Deolinda Rodrigues Pereira; Motta,Carlos Henrique Ares Silveira da; Furtado,Juliana Braga; Bacal,Nydia Strachman; Silveira,Paulo Augusto Achucarro; Moyses,Cynthia Bachir; Sitnik,Roberta; Pinho,João Renato Rebello

    2011-01-01

    Objective: To study the frequency of mutations that may lead to a good or bad prognosis, as well as their relation with the karyotype and immunophenotype in patients with acute myeloid leukemia. Methods: Thirty samples of patients with acute myeloid leukemia were studied, in which FLT3-ITD, FLT3-TKD and NPM1 mutations were investigated. All samples were submitted to immunophenotyping and 25 to karyotyping. Results: An occurrence of 33.3% NPM1 mutation and an equal number of FLT3-ITD mutatio...

  18. Characterization of miRNomes in acute and chronic myeloid leukemia cell lines.

    Science.gov (United States)

    Xiong, Qian; Yang, Yadong; Wang, Hai; Li, Jie; Wang, Shaobin; Li, Yanming; Yang, Yaran; Cai, Kan; Ruan, Xiuyan; Yan, Jiangwei; Hu, Songnian; Fang, Xiangdong

    2014-04-01

    Myeloid leukemias are highly diverse diseases and have been shown to be associated with microRNA (miRNA) expression aberrations. The present study involved an in-depth miRNome analysis of two human acute myeloid leukemia (AML) cell lines, HL-60 and THP-1, and one human chronic myeloid leukemia (CML) cell line, K562, via massively parallel signature sequencing. mRNA expression profiles of these cell lines that were established previously in our lab facilitated an integrative analysis of miRNA and mRNA expression patterns. miRNA expression profiling followed by differential expression analysis and target prediction suggested numerous miRNA signatures in AML and CML cell lines. Some miRNAs may act as either tumor suppressors or oncomiRs in AML and CML by targeting key genes in AML and CML pathways. Expression patterns of cell type-specific miRNAs could partially reflect the characteristics of K562, HL-60 and THP-1 cell lines, such as actin filament-based processes, responsiveness to stimulus and phagocytic activity. miRNAs may also regulate myeloid differentiation, since they usually suppress differentiation regulators. Our study provides a resource to further investigate the employment of miRNAs in human leukemia subtyping, leukemogenesis and myeloid development. In addition, the distinctive miRNA signatures may be potential candidates for the clinical diagnosis, prognosis and treatment of myeloid leukemias. Copyright © 2014. Production and hosting by Elsevier Ltd.

  19. A 78-year-old man with acute myeloid leukemia (AML) and acute renal failure.

    Science.gov (United States)

    Tapper, Elliot B; Luptakova, Katarina; Joyce, Robin M; Tzachanis, Dimitrios

    2014-08-30

    Male, 78. Acute myeloid leukemia (AML). Dyspnea • fatigue. Idarubicin followed by cytarabine. Chemotherapy. Hematology. Unusual clinical course. Renal failure is a common presentation of acute myelomonocytic and monocytic leukemia. It is usually the result of a combined glomerular and tubular dysfunction and is associated with a poor prognosis. No guidelines exist for treatment. We herein describe the case of a 78-year-old Caucasian man who presented with acute myeloid leukemia M5, leukostasis with a white count of 340 000/ml, and acute renal failure with a creatinine of 7.7/dL. The patient was initially treated with leukapheresis and 3 days of idarubicin in the setting of continuous renal replacement therapy that resulted in rapid reversal of his renal failure. He then received 7 days of continuous infusion cytarabine and went into a complete remission. Renal failure may complicate the presentation of AML but can be reversible with treatment. Dose adjustment of the chemotherapy is not needed and the treatment can be greatly facilitated with the use of continuous renal replacement therapy, as indicated in our case report. In addition, we emphasize that organ dysfunction, even in elderly patients, is not necessarily a contraindication to aggressive treatment if it is felt to be disease-related and reversible.

  20. INCIDENCE OF ACUTE MYELOID LEUKEMIA AFTER BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Caterina Giovanna Valentini

    2011-12-01

    Full Text Available Breast cancer is the most frequent cancer among women and the leading cause of death among middle-aged women. Early detection by mammography screening and improvement of therapeutic options have increased breast cancer survival rates, with the consequence that late side effects of cancer treatment become increasingly important. In particular, patients treated with adjuvant chemotherapy regimens, commonly including alkylating agents and anthracyclines, are at increased risk of developing leukemia, further enhanced by the use of radiotherapy. In the last few years also the use of growth factors seems to increase the risk of secondary leukemia. The purpose of this review is to update epidemiology of therapy-related myeloid neoplasms occurring in breast cancer patients

  1. Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials.

    Science.gov (United States)

    Pollyea, Daniel A; Gutman, Jonathan A; Gore, Lia; Smith, Clayton A; Jordan, Craig T

    2014-08-01

    Despite an increasingly rich understanding of its pathogenesis, acute myeloid leukemia remains a disease with poor outcomes, overwhelmingly due to disease relapse. In recent years, work to characterize the leukemia stem cell population, the disease compartment most difficult to eliminate with conventional therapy and most responsible for relapse, has been undertaken. This, in conjunction with advances in drug development that have allowed for increasingly targeted therapies to be engineered, raises the hope that we are entering an era in which the leukemia stem cell population can be eliminated, resulting in therapeutic cures for acute myeloid leukemia patients. For these therapies to become available, they must be tested in the setting of clinical trials. A long-established clinical trials infrastructure has been employed to shepherd new therapies from proof-of-concept to approval. However, due to the unique features of leukemia stem cells, drugs that are designed to specifically eliminate this population may not be adequately tested when applied to this model. Therefore, in this review article, we seek to identify the relevant features of acute myeloid leukemia stem cells for clinical trialists, discuss potential strategies to target leukemia stem cells, and propose a set of guidelines outlining the necessary elements of clinical trials to allow for the successful testing of stem cell-directed therapies. Copyright© Ferrata Storti Foundation.

  2. A Case of Acute Myeloid Leukemia (FAB M2 with Inversion 16 Who Presented with Pelvic Myeloid Sarcoma

    Directory of Open Access Journals (Sweden)

    Mustafa Çakan

    2014-01-01

    Full Text Available Acute leukemias are the most common childhood cancer in all age groups. Acute myeloid leukemias (AML constitute about 15–20% of acute leukemias. Fatigability, pallor, fever, and bleeding are the most common presenting symptoms of AML. Hepatosplenomegaly and lymphadenopathy are commonly encountered during physical examination. In rare instances eruptions due to skin involvement and localized tumor masses (myeloid sarcoma may be found. Myeloid sarcoma is especially seen in AML-M2 subtype. By cytogenetic analysis, in AML-M2 subtype t(8;21 is often seen and it is more probable to find inversion 16 in AML-M4Eos subtype. Herein, we present a 15-year-old girl whose initial symptom was abdominal pain for three days and her pathological sign was a large abdominal mass which was verified by imaging studies and diagnosed as myeloid sarcoma by biopsy. On bone marrow examination, she had diagnosis of AML-M2 and by cytogenetic analysis inversion 16 was positive. She was treated with AML-BFM 2004 protocol and she is being followed up in remission on her ninth month of the maintenance therapy.

  3. Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia.

    Science.gov (United States)

    Abu-Arja, Rolla F; Chernin, Leah R; Abusin, Ghada; Auletta, Jeffery; Cabral, Linda; Egler, Rachel; Ochs, Hans D; Torgerson, Troy R; Lopez-Guisa, Jesus; Hostoffer, Robert W; Tcheurekdjian, Haig; Cooke, Kenneth R

    2015-09-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19(+) B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient's leukemia. © 2015 Wiley Periodicals, Inc.

  4. Detection of anti-Toxoplasma gondii antibodies in chronic myeloid leukemia and acute myeloid leukemia patients

    Directory of Open Access Journals (Sweden)

    Mohammad Javad Gharavi

    2017-09-01

    Full Text Available Background and Aim: Infection of Toxoplasma gondii is a worldwide distribution. Toxoplasmosis in patients who are immunocompromised by virtue of underlying leukemia disease has received relatively little attention. This study was aimed to evaluate IgG and IgM antibodies of T. gondii and to minimize the role of T. gondii and opportunistic infection complication at the early stage of infection in leukemia patients. Materials and Methods: The purpose of this assay was to measure anti-T. gondii IgG and IgM antibodies by enzyme-linked immunosorbent assay (ELISA technique in leukemia patients. Results: IgG antibodies against T. gondii were detected by ELISA in 96 (56.4% leukemia patients and 72 (42.4% control group. IgM antibodies were found in 10 patients (5.9% with leukemia and 3 (1.8% in the corresponding. Conclusion: Our finding indicated that leukemia patients under immunosuppressive condition should not be neglected. Toxoplasmosis in leukemia patients as a main risk factor is considered, meanwhile in some patients, due to possibility of the presence of secondary infection that leads to severe toxoplasmosis.

  5. Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations

    NARCIS (Netherlands)

    K.S. Kramarzova (Karolina Skvarova); K. Fiser (Karel); E. Mejstříková (Ester); K. Rejlova (Katerina); M. Zaliova (Marketa); M.W.J. Fornerod (Maarten); H.A. Drabkin (Harry); M.M. van den Heuvel-Eibrink (Marry); J. Stary (Jan); J. Trka (Jan); J. Starkova (Julia)

    2014-01-01

    markdownabstract__Background:__ Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or

  6. C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

    Czech Academy of Sciences Publication Activity Database

    Alberich-Jorda, M.; Wouters, B.; Balaštík, Martin; Shapiro-Koss, C.; Zhang, H.; DiRuscio, A.; Radomska, H.S.; Ebralidze, A.K.; Amabile, G.; Ye, M.; Zhang, J.Y.; Lowers, I.; Avellino, R.; Melcnick, A.; Figueroa, M.E.; Valk, P.J.M.; Delwel, R.; Tenen, D.G.

    2012-01-01

    Roč. 122, č. 12 (2012), s. 4490-4504 ISSN 0021-9738 Grant - others:NIH(US) CA118316; NIH(US) HL56745 Institutional support: RVO:68378050 Keywords : C/EBP transcription factor * acute myeloid leukemia * differentiation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 12.812, year: 2012

  7. Monosomal karyotype in acute myeloid leukemia: A better indicator of poor prognosis than a complex karyotype

    NARCIS (Netherlands)

    Breems, Dimitri A.; van Putten, Wim L. J.; de Greef, Georgine E.; van Zelderen-Bhola, Shama L.; Gerssen-Schoorl, Klasien B. J.; Mellink, Clemens H. M.; Nieuwint, Aggie; Jotterand, Martine; Hagemeijer, Anne; Beverloo, H. Berna; Lowenberg, Bob

    2008-01-01

    Purpose To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML). Patients and Methods Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years. Results Besides AML with normal cytogenetics (CN)

  8. Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia

    NARCIS (Netherlands)

    Balgobind, Brian V.; Van den Heuvel-Eibrink, Marry M.; De Menezes, Renee X.; Reinhardt, Dirk; Hollink, Iris H. I. M.; Arentsen-Peters, Susan T. J. C. M.; van Wering, Elisabeth R.; Kaspers, Gertjan J. L.; Cloos, Jacqueline; de Bont, Evelien S. J. M.; Cayuela, Jean-Michel; Baruchel, Andre; Meyer, Claus; Marschalek, Rolf; Trka, Jan; Stary, Jan; Beverloo, H. Berna; Pieters, Rob; Zwaan, C. Michel; den Boer, Monique L.

    Background Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity. Design and Methods We examined the

  9. Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia

    NARCIS (Netherlands)

    B.V. Balgobind (Brian); M.M. van den Heuvel-Eibrink (Marry); R.X. de Menezes (Renee); D. Reinhardt (Dirk); I.H.I.M. Hollink (Iris); S.T.C.J.M. Arentsen-Peters (Susan); E.R. van Wering (Elisabeth); G.J. Kaspers (Gertjan); J. Cloos (Jacqueline); E.S.J.M. de Bont (Eveline); J.M. Cayuela (Jean Michel); A. Baruchel (André); C. Meyer (Claus); R. Marschalek (Rolf); J. Trka (Jan); J. Stary (Jan); H.B. Beverloo (Berna); R. Pieters (Rob); C.M. Zwaan (Christian Michel); M.L. den Boer (Monique)

    2011-01-01

    textabstractBackground Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity. Design and Methods We

  10. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

    NARCIS (Netherlands)

    Balgobind, B. V.; Lugthart, S.; Hollink, I. H.; Arentsen-Peters, S. T. J. C. M.; van Wering, E. R.; Reinhardt, D.; Creutzig, U.; Kaspers, G. J. L.; de Bont, E. S. J. M.; Stary, J.; Trka, J.; Zimmermann, M.; Beverloo, H. B.; Pieters, R.; Delwel, R.; Zwaan, C. M.; van den Heuvel-Eibrink, M. M.

    Overexpression of the ecotropic virus integration-1 (EVI1) gene (EVI1+), localized at chromosome 3q26, is associated with adverse outcome in adult acute myeloid leukemia (AML). In pediatric AML, 3q26 abnormalities are rare, and the role of EVI1 is unknown. We studied 228 pediatric AML samples for

  11. Treatment-related Myelodysplastic Syndrome in a Child With Acute Myeloid Leukemia and TPMT Heterozygosity

    DEFF Research Database (Denmark)

    Stensman, Lars M; Kjeldsen, Eigil; Nersting, Jacob

    2014-01-01

    INTRODUCTION: We describe a patient diagnosed with acute myeloid leukemia (AML) and low activity of thiopurine methyltransferase (TPMT) who developed secondary myelodysplastic syndrome after treatment. OBSERVATION: A 10-year-old boy presented with AML-M2 with t(8;21)(q22;q22) and genotyping...

  12. Sox4 is a key oncogenic target in C/EBP alpha mutant acute myeloid leukemia

    Czech Academy of Sciences Publication Activity Database

    Zhang, H.; Alberich-Jorda, Meritxell; Amabile, G.; Yang, H.; Staber, P.B.; DiRuscio, A.; Welner, R.S.; Ebralidze, A.; Zhang, J.; Levantini, E.; Lefebvre, V.; Valk, P.J.; Delwel, R.; Hoogenkamp, M.; Nerlov, C.; Cammenga, J.; Saez, B.; Scadden, D.T.; Bonifer, C.; Ye, M.; Tenen, D.G.

    2013-01-01

    Roč. 24, č. 5 (2013), s. 575-588 ISSN 1535-6108 R&D Projects: GA MŠk LK21307 Institutional support: RVO:68378050 Keywords : Sox4 * C/EBP alpha * acute myeloid leukemia Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 23.893, year: 2013

  13. Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only

    DEFF Research Database (Denmark)

    Molgaard-Hansen, Lene; Glosli, Heidi; Jahnukainen, Kirsi

    2011-01-01

    More than 60% of children with acute myeloid leukemia (AML) become long-term survivors, and approximately 50% are cured with chemotherapy only. Limited data exist about their long-term morbidity and social outcomes. The aim of the study was to compare the self-reported use of health care services...

  14. Inhibition of autophagy as a treatment strategy for p53 wild-type acute myeloid leukemia

    NARCIS (Netherlands)

    Folkerts, Hendrik; Hilgendorf, Susan; Wierenga, Albertus T J; Jaques, Jennifer; Mulder, André B; Coffer, Paul J; Schuringa, Jan Jacob; Vellenga, Edo

    2017-01-01

    Here we have explored whether inhibition of autophagy can be used as a treatment strategy for acute myeloid leukemia (AML). Steady-state autophagy was measured in leukemic cell lines and primary human CD34(+) AML cells with a large variability in basal autophagy between AMLs observed. The autophagy

  15. Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy

    NARCIS (Netherlands)

    Dubois, V.; Sloan-Bena, F.; Cesbron, A.; Hepkema, B. G.; Gagne, K.; Gimelli, S.; Heim, D.; Tichelli, A.; Delaunay, J.; Drouet, M.; Jendly, S.; Villard, J.; Tiercy, J-M

    Although acquired uniparental disomy (aUPD) has been reported in relapse acute myeloid leukemia (AML), pretransplant aUPD involving chromosome 6 is poorly documented. Such events could be of interest because loss of heterozygosity (LOH) resulting from aUPD in leukemic cells may lead to erroneous

  16. C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

    NARCIS (Netherlands)

    M. Alberich-Jorda (Meritxell); B.J. Wouters (Bas); M. Balastik (Martin); C. Shapiro-Koss (Clara); H. Zhang (Hong); A. DiRuscio (Annalisa); H.S. Radomska (Hanna); A. Ebralidze (Alexander); G. Amabile (Giovanni); M. Ye (Min); J. Zhang (Junyan); I. Lowers (Irene); R. Avellino (Roberto); A. Melnick (Ari); M.E. Figueroa (Maria Eugenia); P.J.M. Valk (Peter); H.R. Delwel (Ruud); D.G. Tenen (Daniel)

    2012-01-01

    textabstractC/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was

  17. Single institute study of FLT3 mutation in acute myeloid leukemia ...

    Indian Academy of Sciences (India)

    FLT3/ITD mutation; p53 tumor suppressor gene; NRAS gene; acute myeloid leukemia (AML); tetraploidy/near-tetraploidy; human genetics. ... Institute of Hematology, Medical School, 11000 Belgrade, Serbia; Institute of Molecular Genetics and Genetic Engineering, Medical School, 11000 Belgrade, Serbia; Institute of ...

  18. Classification of pediatric acute myeloid leukemia based on miRNA expression profiles

    NARCIS (Netherlands)

    A. Obulkasim (Askar); J.E. Katsman-Kuipers (Jenny); P. Verboon (Peter); M.A. Sanders (Mathijs); I.P. Touw (Ivo); M. Jongen-Lavrencic (Mojca); R. Pieters (Rob); J.-H. Klusmann; C.M. Zwaan (Christian Michel); M.M. van den Heuvel-Eibrink (Marry); M.W.J. Fornerod (Maarten)

    2017-01-01

    textabstractPediatric acute myeloid leukemia (AML) is a heterogeneous disease with respect to biology as well as outcome. In this study, we investigated whether known biological subgroups of pediatric AML are reflected by a common microRNA (miRNA) expression pattern. We assayed 665 miRNAs on 165

  19. Common and Overlapping Oncogenic Pathways Contribute to the Evolution of Acute Myeloid Leukemias

    NARCIS (Netherlands)

    Kvinlaug, Brynn T.; Chan, Wai-In; Bullinger, Lars; Ramaswami, Mukundhan; Sears, Christopher; Foster, Donna; Lazic, Stanley E.; Okabe, Rachel; Benner, Axel; Lee, Benjamin H.; De Silva, Inusha; Valk, Peter J. M.; Delwel, Ruud; Armstrong, Scott A.; Doehner, Hartmut; Gilliland, D. Gary; Huntly, Brian J. P.

    2011-01-01

    Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or

  20. A study of KIT activating mutations in acute myeloid leukemia M0 ...

    African Journals Online (AJOL)

    Acute Myeloid Leukemia (AML)-M0 is a cancer of blood-forming cells in the bone marrow. KIT gene is a receptor tyrosine kinase class III that is expressed on by early hematopoietic progenitor cells and plays an important role in hematopoietic stem cell proliferation, differentiation and survival. Mutations of KIT receptor ...

  1. Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?

    Directory of Open Access Journals (Sweden)

    Federico Mosna

    2017-06-01

    Full Text Available Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in “real-life” practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia.

  2. Malignant pleural effusion in acute myeloid leukemia with hepatitis B virus infection.

    Science.gov (United States)

    Suharti, C; Santosa; Setiawan, Budi

    2015-04-01

    Pleural effusions can be the first presentation of a hematologic malignancy. The most common disorders with pleural effusion are Hodgkin and non-Hodgkin lymphoma with a frequency of 20 to 30%, especially if mediastinal involvement. Acute and chronic leukemia are rarely accompanied by pleural involvement. We describe a 46-year-old female with history of progressive dyspnoea. Physical examination was revealed massive left pleural effusion. Complete blood count revealed anemia, trombositopenia and normal leucocyte count. Viral serology test shown positive of HBsAg and total antiHBc. Chest X-ray revealed left pleural effusion. Pleural fluid cytology was myeloblast consistent with acute myeloid leukemia (AML). Bone marrow aspiration smear, bone marrow biopsy smear, and flow cytometry analysis were consistent with acute myeloid leukemia without maturation (AML M0-FAB classification).

  3. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

    DEFF Research Database (Denmark)

    Kirstetter, Peggy; Schuster, Mikkel B; Bereshchenko, Oksana

    2008-01-01

    Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p...... penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML....

  4. High expression of lnc-CRNDE presents as a biomarker for acute myeloid leukemia and promotes the malignant progression in acute myeloid leukemia cell line U937.

    Science.gov (United States)

    Wang, Y; Zhou, Q; Ma, J-J

    2018-02-01

    To detect the expression of long non-coding RNA-CRNDE in patients with acute myeloid leukemia and its effect on proliferation and apoptosis in acute myeloid leukemia cell line U937. 81 cases of newly diagnosed acute myeloid leukemia (AML) were enrolled, and 35 non-malignant hematological patients were selected as controls. Quantitative RT-PCR (qRT-PCR) was performed to detect the expression of lncRNA-CRNDE in the bone marrow specimens of the subjects, and the difference between the two groups was also compared. The correlation between the expression of lncRNA-CRNDE and the sex, age, classification and total survival of clinical patients was analyzed according to the clinical data. U937 cells and monocytes isolated from normal people were cultured, and the expression of lncRNA-CRNDE in acute myeloid leukemia cell line U937 and normal monocytes was compared. SiRNA-CRNDE and pcDNA-CRNDE were transfected into U937 cells, and cell counting kit-8 (CCK-8) assay was performed to detect proliferation of U937 cells, Annexin V/PI flow cytometry was carried out to detect cell apoptosis. Cell cycle was measured by flow cytometry. The expression of lncRNA-CRNDE in patients with AML and U937 cells was significantly higher than that in non-malignant hematological controls. Results of clinical data showed that the expression of lncRNA-CRNDE was associated with the classification and total survival of myeloid leukemia in clinical patients. After transfection of siRNA-CRNDE, the proliferation and cloning ability of U937 cells decreased, while the apoptosis increased (p < 0.01) and cells were arrested in G0-G1 phase. Meanwhile, after transfection of pcDNA-CRNDE, the proliferation ability of U937 cells increased significantly, which indicated that the expression of lncRNA-CRNDE might play an essential role in promoting the proliferation of U937 cells. LncRNA-CRNDE is highly expressed in the bone marrow tissues of AML patients, and the expression level is negatively correlated with the

  5. Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia

    DEFF Research Database (Denmark)

    Granfeldt Østgård, Lene Sofie; Medeiros, Bruno C; Sengeløv, Henrik

    2015-01-01

    PURPOSE: Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained...... by differences in karyotype and/or age. PATIENTS AND METHODS: In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic...... leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified...

  6. Molecular Analysis of Gene Rearrangements and Mutations in Acute Leukemias and Myeloid Neoplasms.

    Science.gov (United States)

    Sholl, Lynette M; Longtine, Janina; Kuo, Frank C

    2017-01-11

    A subset of acute leukemias and other myeloid neoplasms contains specific genetic alterations, many of which are associated with unique clinical and pathologic features. These alterations include chromosomal rearrangements leading to oncogenic fusion proteins or alteration of gene expression by juxtaposing oncogenes to enhancer elements, as well as mutations leading to aberrant activation of a variety of proteins critical to hematopoietic progenitor cell proliferation and differentiation. Molecular analysis is central to diagnosis and clinical management of leukemias, permitting genetic confirmation of a clinical and histologic impression, providing prognostic and predictive information, and facilitating detection of minimal residual disease. This unit will outline approaches to the molecular diagnosis of the most frequent and clinically relevant genetic alterations in acute leukemias and myeloid neoplasms. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  7. Development of acute myeloid leukemia in patients with untreated chronic lymphocytic leukemia.

    Science.gov (United States)

    Ito, Shoko; Fujiwara, Shin-Ichiro; Mashima, Kiyomi; Umino, Kento; Minakata, Daisuke; Nakano, Hirofumi; Yamasaki, Ryoko; Kawasaki, Yasufumi; Sugimoto, Miyuki; Ashizawa, Masahiro; Yamamoto, Chihiro; Hatano, Kaoru; Okazuka, Kiyoshi; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kanda, Yoshinobu

    2017-05-01

    The development of acute myeloid leukemia (AML) in patients with untreated chronic lymphocytic leukemia (CLL) is rare. We experienced a 65-year-old man who developed AML with aberrant CD7 expression and monoallelic CEBPA mutation during watchful waiting for CLL. He failed to achieve complete response (CR) by standard induction therapy for AML. We retrospectively reviewed 27 patients who developed AML with untreated CLL published between 1973 and 2016. The median age at diagnosis of AML was 68 years, and the median duration between the diagnoses of AML and CLL was 4.2 years. Diagnosis of AML and CLL was made simultaneously in 16 patients. The CR rate of AML was 42.9%, and the median survival was only 1.5 months after the diagnosis of AML. Patients who achieved CR tended to survive longer than those who did not. Our results demonstrated that the development of AML in patients with untreated CLL was associated with a poor response to chemotherapy and an extremely poor prognosis.

  8. A novel application of furazolidone: anti-leukemic activity in acute myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Xueqing Jiang

    Full Text Available Acute myeloid leukemia (AML is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis and exemplifies a genetically heterogeneous disease. The patients with AML also show a heterogeneous response to therapy. Although all-trans retinoic acid (ATRA has been successfully introduced to treat acute promyelocytic leukemia (APL, it is rather ineffective in non-APL AML. In our present study, 1200 off-patent marketed drugs and natural compounds that have been approved by the Food and Drug Administration (FDA were screened for anti-leukemia activity using the retrovirus transduction/transformation assay (RTTA. Furazolidone (FZD was shown to inhibit bone marrow transformation mediated by several leukemia fusion proteins, including AML1-ETO. Furazolidone has been used in the treatment of certain bacterial and protozoan infections in human and animals for more than sixty years. We investigated the anti-leukemic activity of FZD in a series of AML cells. FZD displayed potent antiproliferative properties at submicromolar concentrations and induced apoptosis in AML cell lines. Importantly, FZD treatment of certain AML cells induced myeloid cell differentiation by morphology and flow cytometry for CD11b expression. Furthermore, FZD treatment resulted in increased stability of tumor suppressor p53 protein in AML cells. Our in vitro results suggest furazolidone as a novel therapeutic strategy in AML patients.

  9. Integration of gene expression and DNA-methylation profiles improves molecular subtype classification in acute myeloid leukemia

    NARCIS (Netherlands)

    Taskesen, E.; Babaei, S.; Reinders, M.J.M.; De Ridder, J.

    2015-01-01

    Background Acute Myeloid Leukemia (AML) is characterized by various cytogenetic and molecular abnormalities. Detection of these abnormalities is important in the risk-classification of patients but requires laborious experimentation. Various studies showed that gene expression profiles (GEP), and

  10. Diagnosis of chronic myeloid and acute lymphocytic leukemias by detection of leukemia-specific mRNA sequences amplified in vitro

    International Nuclear Information System (INIS)

    Kawasaki, E.S.; Clark, S.S.; Coyne, M.Y.; Smith, S.D.; Champlin, R.; Witte, O.N.; McCormick, F.P.

    1988-01-01

    The Philadelphia chromosome is present in more than 95% of chronic myeloid leukemia patients and 13% of acute lymphocytic leukemia patients. The Philadelphia translocation, t(9;22), fuses the BCR and ABL genes resulting in the expression of leukemia-specific, chimeric BCR-ABL messenger RNAs. To facilitate diagnosis of these leukemias, the authors have developed a method of amplifying and detecting only the unique mRNA sequences, using an extension of the polymerase chain reaction technique. Diagnosis of chronic myeloid and acute lymphocytic leukemias by this procedure is rapid, much more sensitive than existing protocols, and independent of the presence or absence of an identifiable Philadelphia chromosome

  11. Myeloid Sarcoma after Allogenic Stem Cell Transplantation for Acute Myeloid Leukemia: Successful Consolidation Treatment Approaches in Two Patients

    Directory of Open Access Journals (Sweden)

    Silje Johansen

    2018-01-01

    Full Text Available Myeloid sarcoma is an extramedullary (EM manifestation (i.e., manifestation outside the bone marrow of acute myeloid leukemia (AML; it is assumed to be relatively uncommon and can be the only manifestation of leukemia relapse after allogenic stem cell transplantation (allo-SCT. An EM sarcoma can manifest in any part of the body, although preferentially manifesting in immunological sanctuary sites as a single or multiple tumors. The development of myeloid sarcoma after allo-SCT is associated with certain cytogenetic abnormalities, developing of graft versus host disease (GVHD, and treatment with donor lymphocytes infusion (DLI. It is believed that posttransplant myeloid sarcomas develop because the EM sites evade immune surveillance. We present two patients with EM myeloid sarcoma in the breast and epipharynx, respectively, as the only manifestation of leukemia relapse. Both patients were treated with a combination of local and systemic therapy, with successfully longtime disease-free survival. Based on these two case reports, we give an updated review of the literature and discuss the pathogenesis, diagnosis, and treatment of EM sarcoma as the only manifestation of AML relapse after allo-SCT. There are no standard guidelines for the treatment of myeloid sarcomas in allotransplant recipients. In our opinion, the treatment of these patients needs to be individualized and should include local treatment (i.e., radiotherapy combined with systemic therapy (i.e., chemotherapy, immunotherapy, DLI, or retransplantation. The treatment has to consider both the need for sufficient antileukemic efficiency versus the risk of severe complications due to cumulative toxicity.

  12. Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.

    Science.gov (United States)

    Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P; Snyder, David S; Khoury, Jean; Bhalla, Kapil N; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C; Rutkoski, Thomas J; Smith, Bryan D; Flynn, Daniel L; Kantarjian, Hagop M; Rosen, Oliver; Van Etten, Richard A

    2017-03-01

    A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib ( clinicaltrials.gov Identifier:00827138 ). Copyright© Ferrata Storti Foundation.

  13. Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation

    International Nuclear Information System (INIS)

    Wang, Ya-Fei; Li, Qian; Xu, Wen-Gui; Xiao, Jian-Yu; Pang, Qing-Song; Yang, Qing; Zhang, Yi-Zuo

    2013-01-01

    Myeloid sarcoma (MS) is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia (AML). This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission. A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010. After one month, bone marrow biopsy and aspiration confirmed the diagnosis of AML. Allogeneic mobilization peripheral blood stem cell transplantation was performed, with the sister of the patient as donor, after complete remission (CR) was achieved by chemotherapy. Five months after treatment, an adrenal mass was detected by positron emission tomography-computed tomography (PET-CT). Radiotherapy was performed for the localized mass after a multidisciplinary team (MDT) discussion. The patient is still alive as of May 2013, with no evidence of recurrent MS or leukemia

  14. Targeted Therapies in Hematology and Their Impact on Patient Care: Chronic and Acute Myeloid Leukemia

    Science.gov (United States)

    Cortes, Elias Jabbour Jorge; Ravandi, Farhad; O’Brien, Susan; Kantarjian, Hagop

    2014-01-01

    Advances in the genetic and molecular characterizations of leukemias have enhanced our capabilities to develop targeted therapies. The most dramatic examples of targeted therapy in cancer to date are the use of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI) which has revolutionized the treatment of chronic myeloid leukemia (CML). Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target, transforming the prognosis of patients with CML. In contrast, acute myeloid leukemia (AML) is an extremely heterogeneous disease with outcomes that vary widely according to subtype of the disease. Targeted therapy with monoclonal antibodies and small molecule kinase inhibitors are promising strategies to help improve the cure rates in AML. In this review, we will highlight the results of recent clinical trials in which outcomes of CML and AML have been influenced significantly. Also, novel approaches to sequencing and combining available therapies will be covered. PMID:24246694

  15. Molecular and cytogenetic abnormalities in acute myeloid leukemia: review and case studies

    Directory of Open Access Journals (Sweden)

    Elvira Deolinda Rodrigues Pereira Velloso

    2011-06-01

    Full Text Available Objective: To study the frequency of mutations that maylead to a good or bad prognosis, as well as their relation withthe karyotype and immunophenotype in patients with acutemyeloid leukemia. Methods: Thirty samples of patients withacute myeloid leukemia were studied, in which FLT3-ITD, FLT3-TKD and NPM1 mutations were investigated. All samples weresubmitted to immunophenotyping and 25 to karyotyping. Results:An occurrence of 33.3% NPM1 mutation and an equal numberof FLT3-ITD mutation were observed. When only the cases withnormal karyotype were studied, this figures increased to 50 and40%, respectively. Eight percent of cases with normal karyotypeand genotype NPM1+/FLT3- were included in the group of acutemyeloid leukemia with good prognosis. The typical phenotypeof acute myeloid leukemia with normal karyotype and mutatedNPM1 (HLA-DR and CD34 negative was not observed in thissmall series. Conclusion: Good prognosis cases were identifiedin this series, emphasizing the need to include new geneticmarkers in the diagnostic routine for the correct classification ofacute myeloid leukemia, to more properly estimate prognosis anddetermine treatment.

  16. Pediatric acute myeloid leukemia: biology and therapeutic implications of genomic variants.

    Science.gov (United States)

    Tarlock, Katherine; Meshinchi, Soheil

    2015-02-01

    Acute myeloid leukemia (AML) is a molecularly heterogeneous disease and age-associated molecular alterations result in younger children harboring a distinct signature from older children and adolescents. Pediatric AML has a genetic and epigenetic profile with significant differences compared to adult AML. Somatic and epigenetic alterations contribute to myeloid leukemogenesis and can evolve from diagnosis to relapse. Cytogenetic alterations, somatic mutations and response to induction therapy are important in informing risk stratification and appropriate therapy allocation. Next-generation sequencing technologies are providing novel insights into the biology of AML and have the ability to identify potential targets for therapeutic intervention. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Outpatient Management Following Intensive Induction or Salvage Chemotherapy for Acute Myeloid Leukemia

    OpenAIRE

    Walter, Roland B.; Taylor, Lenise R.; Gardner, Kelda M.; Dorcy, Kathleen Shannon; Vaughn, Jennifer E.; Estey, Elihu H.

    2013-01-01

    Adults with newly diagnosed or relapsed acute myeloid leukemia (AML) commonly receive intensive chemotherapy to achieve disease remission. In the United States and many other countries, it is standard practice that these patients remain hospitalized “preemptively” until blood count recovery due to the risk for overwhelming infections and bleeding during pancytopenia. This care policy requires hospitalization for an average of 3–4 weeks after completion of chemotherapy. However, highly effecti...

  18. Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia: a Single-Centre Experience

    Directory of Open Access Journals (Sweden)

    Kakucs Enikő

    2013-04-01

    Full Text Available Introduction: Autologous haemopoietic stem cell transplantation (SCT is an important treatment modality for patients with acute myeloid leukemia with low and intermediate risk disease. It has served advantages over allogenic transplantation, because it does not need a matched donor, there is no graft versus host disease, there are less complications and a faster immune reconstitution than in the allo-setting. The disadvantage is the lack of the graft versus leukaemia effect.

  19. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Burnett, Alan; Cavenagh, Jamie; Russell, Nigel

    2016-01-01

    Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose.......17-3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs 0.5%; Pcombination with induction chemotherapy when...

  20. Prognostic Value of a CYP2B6 Gene Polymorphism in Patients with Acute Myeloid Leukemia.

    Science.gov (United States)

    Alazhary, Nevin M; Shafik, Roxan E; Shafik, Hanan E; Kamel, Mahmoud M

    2015-01-01

    The objectives of this study aimed to detect a CYP2B6 polymorphism in de novo cases of acute myeloid leukemia patients and identify any role in disease progression and outcome. DNA was isolated from peripheral blood of 82 newly diagnosed acute myeloid leukemia cases and the CYP2B6 G15631T gene polymorphism was assayed by PCR restriction fragment length polymorphism (PCR-RFLP). The frequency of the GG genotype (wild type) was 48 (58.5%) and that of the mutant type T allele was 34 (41.9%). GT genotype heterozygous variants were found in 28 (34%), and TT genotype homozygous variants in 6 (7.3%) cases. We found no significant association between the CYP2B6 G15631T polymorphism and complete response (CR) (p-value=0.768), FAB classification (p-value=0.51), cytogenetic analysis (p-value=0.673), and overall survival (p-value=0.325). Also, there were no significant links with early toxic death (p-value=0.92) or progression- free survival (PFS) (p-value=0.245). Our results suggest that the CYP2B6 polymorphism has no role in disease progression, therapeutic outcome, patient free survival, early toxic death and overall survival in acute myeloid leukemia patients.

  1. NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features

    DEFF Research Database (Denmark)

    Andersen, Morten Tolstrup; Andersen, Mette Klarskov; Christiansen, D.H.

    2008-01-01

    Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t......-/-7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P=0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest...

  2. Chronic meningitis by histoplasmosis: report of a child with acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    G.H. Pereira

    Full Text Available Meningitis is a common evolution in progressive disseminated histoplasmosis in children, and is asymptomatic in many cases. In leukemia, the impaired of the T cells function can predispose to the disseminated form. The attributed mortality rate in this case is 20%-40% and the relapse rate is as high as 50%; therefore, prolonged treatment may be emphasized. We have described a child with acute myeloid leukemia (AML, that developed skin lesions and asymptomatic chronic meningitis, with a good evolution after prolonged treatment with amphotericin B deoxycholate followed by fluconazole.

  3. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1

    NARCIS (Netherlands)

    B.J. Wouters (Bas); M.A. Jordà; K. Keeshan (Karen); I. Louwers (Irene); C.A.J. Erpelinck (Claudia); D. Tielemans; A.W. Langerak (Anton); Y. He (Yiping); Y. Yashiro-Ohtani (Yumi); P. Zhang (Pu); C.J. Hetherington (Christopher); R.G.W. Verhaak (Roel); P.J.M. Valk (Peter); B. Löwenberg (Bob); D.G. Tenen (Daniel); W.S. Pear (Warren); H.R. Delwel (Ruud)

    2007-01-01

    textabstractGene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor

  4. Rare cytogenetic abnormalities and alteration of microRNAs in acute myeloid leukemia and response to therapy

    Directory of Open Access Journals (Sweden)

    Mohammad Shahjahani

    2015-03-01

    Full Text Available Acute myeloid leukemia (AML is the most common acute leukemia in adults, which is heterogeneous in terms of morphological, cytogenetic and clinical features. Cytogenetic abnormalities, including karyotype aberrations, gene mutations and gene expression abnormalities are the most important diagnostic tools in diagnosis, classification and prognosis in acute myeloid leukemias. Based on World Health Organization (WHO classification, acute myeloid leukemias can be divided to four groups. Due to the heterogeneous nature of AML and since most therapeutic protocols in AML are based on genetic alterations, gathering further information in the field of rare disorders as well as common cytogenetic abnormalities would be helpful in determining the prognosis and treatment in this group of diseases. Recently, the role of microRNAs (miRNAs in both normal hematopoiesis and myeloid leukemic cell differentiation in myeloid lineage has been specified. miRNAs can be used instead of genes for AML diagnosis and classification in the future, and can also play a decisive role in the evaluation of relapse as well as response to treatment in the patients. Therefore, their use in clinical trials can affect treatment protocols and play a role in therapeutic strategies for these patients. In this review, we have examined rare cytogenetic abnormalities in different groups of acute myeloid leukemias according to WHO classification, and the role of miRNA expression in classification, diagnosis and response to treatment of these disorders has also been dealt with.

  5. Rare Cytogenetic Abnormalities and Alteration of microRNAs in Acute Myeloid Leukemia and Response to Therapy

    Science.gov (United States)

    Shahjahani, Mohammad; Khodadi, Elahe; Seghatoleslami, Mohammad; Asl, Javad Mohammadi; Golchin, Neda; Zaieri, Zeynab Deris

    2015-01-01

    Acute myeloid leukemia (AML) is the most common acute leukemia in adults, which is heterogeneous in terms of morphological, cytogenetic and clinical features. Cytogenetic abnormalities, including karyotype aberrations, gene mutations and gene expression abnormalities are the most important diagnostic tools in diagnosis, classification and prognosis in acute myeloid leukemias. Based on World Health Organization (WHO) classification, acute myeloid leukemias can be divided to four groups. Due to the heterogeneous nature of AML and since most therapeutic protocols in AML are based on genetic alterations, gathering further information in the field of rare disorders as well as common cytogenetic abnormalities would be helpful in determining the prognosis and treatment in this group of diseases. Recently, the role of microRNAs (miRNAs) in both normal hematopoiesis and myeloid leukemic cell differentiation in myeloid lineage has been specified. miRNAs can be used instead of genes for AML diagnosis and classification in the future, and can also play a decisive role in the evaluation of relapse as well as response to treatment in the patients. Therefore, their use in clinical trials can affect treatment protocols and play a role in therapeutic strategies for these patients. In this review, we have examined rare cytogenetic abnormalities in different groups of acute myeloid leukemias according to WHO classification, and the role of miRNA expression in classification, diagnosis and response to treatment of these disorders has also been dealt with. PMID:26779308

  6. Rare Cytogenetic Abnormalities and Alteration of microRNAs in Acute Myeloid Leukemia and Response to Therapy.

    Science.gov (United States)

    Shahjahani, Mohammad; Khodadi, Elahe; Seghatoleslami, Mohammad; Asl, Javad Mohammadi; Golchin, Neda; Zaieri, Zeynab Deris; Saki, Najmaldin

    2015-02-10

    Acute myeloid leukemia (AML) is the most common acute leukemia in adults, which is heterogeneous in terms of morphological, cytogenetic and clinical features. Cytogenetic abnormalities, including karyotype aberrations, gene mutations and gene expression abnormalities are the most important diagnostic tools in diagnosis, classification and prognosis in acute myeloid leukemias. Based on World Health Organization (WHO) classification, acute myeloid leukemias can be divided to four groups. Due to the heterogeneous nature of AML and since most therapeutic protocols in AML are based on genetic alterations, gathering further information in the field of rare disorders as well as common cytogenetic abnormalities would be helpful in determining the prognosis and treatment in this group of diseases. Recently, the role of microRNAs (miRNAs) in both normal hematopoiesis and myeloid leukemic cell differentiation in myeloid lineage has been specified. miRNAs can be used instead of genes for AML diagnosis and classification in the future, and can also play a decisive role in the evaluation of relapse as well as response to treatment in the patients. Therefore, their use in clinical trials can affect treatment protocols and play a role in therapeutic strategies for these patients. In this review, we have examined rare cytogenetic abnormalities in different groups of acute myeloid leukemias according to WHO classification, and the role of miRNA expression in classification, diagnosis and response to treatment of these disorders has also been dealt with.

  7. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia

    NARCIS (Netherlands)

    F. Dong (Fan); R.K. Brynes; N. Tidow; K. Welte (Karl); B. Löwenberg (Bob); I.P. Touw (Ivo)

    1995-01-01

    textabstractBACKGROUND. In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction

  8. A mathematical model of phosphorylation AKT in Acute Myeloid Leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Adi, Y. A., E-mail: yudi.adi@math.uad.ac.id [Department of Mathematic Faculty of MIPA Universitas Ahmad Dahlan (Indonesia); Department of Mathematic Faculty of MIPA Universitas Gadjah Mada (Indonesia); Kusumo, F. A.; Aryati, L. [Department of Mathematic Faculty of MIPA Universitas Gadjah Mada (Indonesia); Hardianti, M. S. [Department of Internal Medicine, Faculty of Medicine, Universitas Gadjah Mada (Indonesia)

    2016-04-06

    In this paper we consider a mathematical model of PI3K/AKT signaling pathways in phosphorylation AKT. PI3K/AKT pathway is an important mediator of cytokine signaling implicated in regulation of hematopoiesis. Constitutive activation of PI3K/AKT signaling pathway has been observed in Acute Meyloid Leukemia (AML) it caused by the mutation of Fms-like Tyrosine Kinase 3 in internal tandem duplication (FLT3-ITD), the most common molecular abnormality associated with AML. Depending upon its phosphorylation status, protein interaction, substrate availability, and localization, AKT can phosphorylate or inhibite numerous substrates in its downstream pathways that promote protein synthesis, survival, proliferation, and metabolism. Firstly, we present a mass action ordinary differential equation model describing AKT double phosphorylation (AKTpp) in a system with 11 equations. Finally, under the asumtion enzyme catalyst constant and steady state equilibrium, we reduce the system in 4 equation included Michaelis Menten constant. Simulation result suggested that a high concentration of PI3K and/or a low concentration of phospatase increased AKTpp activation. This result also indicates that PI3K is a potential target theraphy in AML.

  9. A mathematical model of phosphorylation AKT in Acute Myeloid Leukemia

    Science.gov (United States)

    Adi, Y. A.; Kusumo, F. A.; Aryati, L.; Hardianti, M. S.

    2016-04-01

    In this paper we consider a mathematical model of PI3K/AKT signaling pathways in phosphorylation AKT. PI3K/AKT pathway is an important mediator of cytokine signaling implicated in regulation of hematopoiesis. Constitutive activation of PI3K/AKT signaling pathway has been observed in Acute Meyloid Leukemia (AML) it caused by the mutation of Fms-like Tyrosine Kinase 3 in internal tandem duplication (FLT3-ITD), the most common molecular abnormality associated with AML. Depending upon its phosphorylation status, protein interaction, substrate availability, and localization, AKT can phosphorylate or inhibite numerous substrates in its downstream pathways that promote protein synthesis, survival, proliferation, and metabolism. Firstly, we present a mass action ordinary differential equation model describing AKT double phosphorylation (AKTpp) in a system with 11 equations. Finally, under the asumtion enzyme catalyst constant and steady state equilibrium, we reduce the system in 4 equation included Michaelis Menten constant. Simulation result suggested that a high concentration of PI3K and/or a low concentration of phospatase increased AKTpp activation. This result also indicates that PI3K is a potential target theraphy in AML.

  10. Genetics Home Reference: acute promyelocytic leukemia

    Science.gov (United States)

    ... Home Health Conditions Acute promyelocytic leukemia Acute promyelocytic leukemia Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Acute promyelocytic leukemia is a form of acute myeloid leukemia, a ...

  11. Frequency of fab subtypes in acute myeloid leukemia patients at Aga Khan University Hospital Karachi.

    Science.gov (United States)

    Harani, Mahadev S; Adil, Salman Naseem; Shaikh, Mohammad Usman; Kakepoto, Ghulam Nabi; Khurshid, Mohammmad

    2005-01-01

    Acute myeloid leukemia (AML) is a heterogeneous disease. Therefore, various parameters are needed to classify this disease into subtypes, so that specific treatment approaches can be utilized effectively. The commonly used method for diagnosis and classification is based on FAB criteria using morphology and cytochemical stains. For some of the categories, immunophenotyping is necessary. The aim of present study is to determine the frequency of various sub types in acute myeloid leukemia using FAB criteria in our population. This will aid in the correct diagnosis of acute leukemia and hence proper management of the patients. This is descriptive case control study conducted at Aga Khan University Hospital from January 1999 to December 2000. The total number of subjects was 116 that included both adults and children. The patients were diagnosed on the basis of bone marrow morphology using FAB classification. Cytochemistry was done in all cases, while immunophenotyping was considered only in those cases that were found to be problematic. Among 116 patients, 70 were males and 46 were females with male to female ratio 1.5:1. The age ranged between 6 months to 85 years with a mean age of 32 years. AML-M4 was the predominant French-American-British (FAB) subtype (36.2%) followed by M2 (30.25%), M3 (10.4%), M1 (8.7%), M0 (7.7%), M5a (3.5%), M5b (2.5%) and M6 (0.8%). The most common FAB subtype observed in our study was Acute myelomonocytic leukemia (M4) which is in accordance with studies reported from Saudia Arabia and a previous study reported from our institution. However,other national and international studies have reported Myeloblastic Leukemia with maturation (M2) as the predominant subtype of AML.

  12. C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

    Science.gov (United States)

    Alberich-Jordà, Meritxell; Wouters, Bas; Balastik, Martin; Shapiro-Koss, Clara; Zhang, Hong; DiRuscio, Annalisa; Radomska, Hanna S.; Ebralidze, Alexander K.; Amabile, Giovanni; Ye, Min; Zhang, Junyan; Lowers, Irene; Avellino, Roberto; Melnick, Ari; Figueroa, Maria E.; Valk, Peter J.M.; Delwel, Ruud; Tenen, Daniel G.

    2012-01-01

    C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs. PMID:23160200

  13. Cytogenetically Unrelated Clones in Acute Myeloid Leukemia Showing Different Responses to Chemotherapy

    Directory of Open Access Journals (Sweden)

    Kohei Kasahara

    2016-01-01

    Full Text Available We report a case of acute myeloid leukemia (AML with two cytogenetically unrelated clones. The patient was a 45-year-old male who was diagnosed with acute monoblastic leukemia (AMoL. Initial G-band analysis showed 51,XY,+6,+8,inv(9(p12q13c,+11,+13,+19[12]/52,idem,+Y[8], but G-band analysis after induction therapy showed 45,XY,-7,inv(9(p12q13c[19]/46,XY,inv(9(p12q13c[1]. Retrospective FISH analysis revealed a cryptic monosomy 7 clone in the initial AML sample. The clone with multiple trisomies was eliminated after induction therapy and never recurred, but a clone with monosomy 7 was still detected in myelodysplastic marrow with a normal blast percentage. Both clones were successfully eliminated after related peripheral blood stem cell transplantation, but the patient died of relapsed AML with monosomy 7. We concluded that one clone was de novo AMoL with chromosome 6, 8, 11, 13, and 19 trisomy and that the other was acute myeloid leukemia with myelodysplasia-related changes (AML-MRC with chromosome 7 monosomy showing different responses to chemotherapy. Simultaneous onset of cytogenetically unrelated hematological malignancies that each have a different disease status is a rare phenomenon but is important to diagnose for a correct understanding of the disease status and for establishing an appropriate treatment strategy.

  14. Sox4 is a key oncogenic target in C/EBPα mutant Acute Myeloid Leukemia

    Science.gov (United States)

    Zhang, Hong; Alberich-Jordà, Meritxell; Amabile, Giovanni; Yang, Henry; Staber, Philipp B.; DiRuscio, Annalisa; Welner, Rob; Ebralidze, Alexander; Zhang, Junyan; Levantini, Elena; Lefebvre, Véronique; Valk, Peter J.M.; Delwel, Ruud; Hoogenkamp, Maarten; Nerlov, Claus; Cammenga, Jörg; Saez, Borja; Scadden, David T.; Bonifer, Constanze

    2014-01-01

    Summary Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype. PMID:24183681

  15. TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia

    DEFF Research Database (Denmark)

    Willer, Anton; Jakobsen, Janus Schou; Ohlsson, E

    2015-01-01

    influence the clinical outcome. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for leukemic maintenance and provide novel insights into the regulatory gene expression circuitries in MLL-rearranged AML.Leukemia......Members of the TALE (three-amino-acid loop extension) family of atypical homeodomain-containing transcription factors are important downstream effectors of oncogenic fusion proteins involving the mixed lineage leukemia (MLL) gene. A well-characterized member of this protein family is MEIS1, which...... orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). TGIF1/TGIF2 are relatively uncharacterized TALE transcription factors, which, in contrast to the remaining family, have been shown to act as transcriptional repressors. Given the general...

  16. Heme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia.

    Science.gov (United States)

    Salerno, Loredana; Romeo, Giuseppe; Modica, Maria N; Amata, Emanuele; Sorrenti, Valeria; Barbagallo, Ignazio; Pittalà, Valeria

    2017-12-15

    Heme oxygenase-1 (HO-1) is the enzyme catalyzing the rate-limiting oxidative degradation of cellular heme into free iron, carbon monoxide (CO), and biliverdin, which is then rapidly converted into bilirubin. By means of these catabolic end-products and by removal of pro-oxidant heme, HO-1 exerts antioxidant, antiapoptotic, and immune-modulating effects, leading to overall cytoprotective and beneficial functions in mammalian cells. Therefore, HO-1 is considered a survival molecule in various stress-related conditions. By contrast, growing evidence suggests that HO-1 is a survival-enhancing molecule also in various solid and blood cancers, such as various types of leukemia, promoting carcinogenesis, tumor progression, and chemo-resistance. Among leukemias, chronic myeloid leukemia (CML) is currently therapeutically well treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM) and its congeners; nevertheless, resistance to all kinds of current drugs persist in a number of patients. Moreover, treatment outcomes for acute myeloid leukemia (AML) remain unsatisfactory, despite progress in chemotherapy and hematopoietic stem cell transplantation. Therefore, identification of new eligible targets that may improve leukemias therapy is of general interest. Several recent papers prove that inhibition of HO-1 through HO-1 inhibitors as well as modulation of other pathways involving HO-1 by a number of different new or known molecules, are critical for leukemia treatment. This review summarizes the current understanding of the pro-tumorigenic role of HO-1 and its potential as a molecular target for the treatment of leukemias. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia.

    Science.gov (United States)

    Wang, Jinghua; Chen, Siyu; Xiao, Wei; Li, Wende; Wang, Liang; Yang, Shuo; Wang, Weida; Xu, Liping; Liao, Shuangye; Liu, Wenjian; Wang, Yang; Liu, Nawei; Zhang, Jianeng; Xia, Xiaojun; Kang, Tiebang; Chen, Gong; Cai, Xiuyu; Yang, Han; Zhang, Xing; Lu, Yue; Zhou, Penghui

    2018-01-10

    Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. The CLL-1 CAR-T cells specifically lysed CLL-1 + cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1 + myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.

  18. Identification of i(X)(p10) as the sole molecular abnormality in atypical chronic myeloid leukemia evolved into acute myeloid leukemia.

    Science.gov (United States)

    Gurnari, Carmelo; Panetta, Paola; Fabiani, Emiliano; Nardone, Anna Maria; Postorivo, Diana; Falconi, Giulia; Franceschini, Luca; Rizzo, Manuela; Rapisarda, Vito Mario; De Bellis, Eleonora; Lo-Coco, Francesco; Voso, Maria Teresa

    2018-03-01

    The World Health Organization classifies atypical chronic myeloid leukemia (aCML) as a myeloproliferative/myelodisplastic hematological disorder. The primary manifestations are leukocytosis with disgranulopoiesis, absence of basophilia and/or monocytosis, splenomegaly and absence of Philadelphia chromosome or BCR/ABL fusion. Overall 50-65% of patients demonstrate karyotypic abnormalities, although no specific cytogenetic alterations have been associated with this disease. X chromosome alterations have been rarely reported in myeloid malignancies. Although Isodicentric X, idic(X)(q13) is well known in females with myelodysplastic syndromes (MDS), little data are available on X isochromosome and its pathogenetic potential in these disorders. i(X)(p10) is observed in a variety of hematologic malignancies, both myeloid and lymphoid, as a unique abnormality, as well as part of a more complex karyotype, in females and less frequently in male patients. The present report describes the first patient with aCML, with documented isolated i(X)(p10), who developed a secondary acute myeloid leukemia (sAML).

  19. Biting back: BiTE antibodies as a promising therapy for acute myeloid leukemia.

    Science.gov (United States)

    Walter, Roland B

    2014-06-01

    The experience with gemtuzumab ozogamicin has highlighted both the potential value and limitations of antibodies in acute myeloid leukemia (AML). Recently, bispecific T-cell engager (BiTE) antibodies have emerged as a means to harness polyclonal cytotoxic T-cells and cause highly efficient lysis of targeted tumor cells. Promising early results have been obtained with the CD19-directed BiTE antibody, blinatumomab, in patients with acute lymphoblastic leukemia. A first candidate for AML is the CD33/CD3 molecule, AMG 330, for which several recent preclinical studies demonstrated high potency and efficacy in destroying CD33(+) human AML cells. Many questions remain to be addressed, but BiTE antibodies may offer an exciting new tool in a disease for which the outcomes in many patients remain unsatisfactory.

  20. Cytarabine and daunorubicin or idarubicin in induction therapy of Acute Myeloid Leukemia patients

    International Nuclear Information System (INIS)

    Eivazi-Ziaei, J.; Kermani, I.A.; Nikanfar, A.; Maljaie, H.; Mahmoudpour, A.; Dolatkhah, R.

    2010-01-01

    Objectives: Acute myeloid leukemia (AML), the most common form of acute leukemia, is treated by remission induction and post-remission therapy. Remission induction is usually achieved by administration of cytarabine along with an anthracycline such as Daunorubicin (DAU) or Idarubicin (IDA). Our objective was see the benefits if any of IDA over DAU in AML therapy. Methodology: Eighty adult AML patients were enrolled in this study, where 40 received DAU and 40 were treated with IDA. Remission status in each subject was studied and response to therapy was subsequently analyzed using SPSS. Results: Complete remission, partial remission and no responsive status were 15, 19, and 14 respectively for patients on DAU and 14, 18, and 11 for patients on IDA protocol. No significant benefit was detected for IDA compared to DAU in response to therapy. Conclusion: We found no benefit in using IDA over DAU in induction therapy for AML patients treated in northwest of Iran. (author)

  1. Granulomatous rosacea: Like leukemid in a patient with acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Škiljević Dušan

    2008-01-01

    Full Text Available Introduction. Skin findings in leukemias may be divided into specific lesions (leukemia cutis and non-specific lesions (leukemids which may be found in up to 80% of all patients with leukemias. The leukemids vary clinically and they are usually a manifestation of bone marrow or immunologic impairment, but also Sweet syndrome, pyoderma gangrenosum, erythroderma, maculopapular exanthema, prurigo-like papules, generalized pigmentation, follicular mucinosis, generalized pruritus may be found during the course of leukemia. Case report. We report a 70-year-old male with a 3-month history of erythema, papules and pustules on the face, ears and neck and over a month history of refractory anemia, anorexia, weight loss, malaise, and fever. Physical examination revealed symmetric erythematous, violaceous papules, papulo-nodules and plaques with slate scale and sparse, small pustules on the face, earlobes and neck. Histopathologic findings of involved skin showed diffuse mixed inflammatory cell infiltrate with perifollicular accentuation and focal granulomatous inflammation in the papillary and upper reticular dermis. Extensive checkup revealed the presence of acute myeloid leukemia French- American-British (FAB classification subtype M2, with signs of three-lineage dysplasia. The patient was treated by L6 protocol which led to complete remission, both in bone marrow and skin, but after seven months he had relapse of leukemia with the fatal outcome. Conclusion. This case indicates the importance of skin eruptions in the context of hematological malignancies.

  2. Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia.

    Science.gov (United States)

    Jankovic, Dragana; Gorello, Paolo; Liu, Ting; Ehret, Sabire; La Starza, Roberta; Desjobert, Cecile; Baty, Florent; Brutsche, Martin; Jayaraman, Padma-Sheila; Santoro, Alessandra; Mecucci, Christina; Schwaller, Juerg

    2008-06-15

    We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1(+)) as well as markers of the B-cell lineage (B220(+)). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets.

  3. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia.

    Science.gov (United States)

    Callens, Celine; Coulon, Séverine; Naudin, Jerome; Radford-Weiss, Isabelle; Boissel, Nicolas; Raffoux, Emmanuel; Wang, Pamella Huey Mei; Agarwal, Saurabh; Tamouza, Houda; Paubelle, Etienne; Asnafi, Vahid; Ribeil, Jean-Antoine; Dessen, Philippe; Canioni, Danielle; Chandesris, Olivia; Rubio, Marie Therese; Beaumont, Carole; Benhamou, Marc; Dombret, Hervé; Macintyre, Elizabeth; Monteiro, Renato C; Moura, Ivan C; Hermine, Olivier

    2010-04-12

    Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML.

  4. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia

    Science.gov (United States)

    Callens, Celine; Coulon, Séverine; Naudin, Jerome; Radford-Weiss, Isabelle; Boissel, Nicolas; Raffoux, Emmanuel; Wang, Pamella Huey Mei; Agarwal, Saurabh; Tamouza, Houda; Paubelle, Etienne; Asnafi, Vahid; Ribeil, Jean-Antoine; Dessen, Philippe; Canioni, Danielle; Chandesris, Olivia; Rubio, Marie Therese; Beaumont, Carole; Benhamou, Marc; Dombret, Hervé; Macintyre, Elizabeth; Monteiro, Renato C.

    2010-01-01

    Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML. PMID:20368581

  5. The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia.

    Science.gov (United States)

    Eisfeld, A-K; Mrózek, K; Kohlschmidt, J; Nicolet, D; Orwick, S; Walker, C J; Kroll, K W; Blachly, J S; Carroll, A J; Kolitz, J E; Powell, B L; Wang, E S; Stone, R M; de la Chapelle, A; Byrd, J C; Bloomfield, C D

    2017-10-01

    Recurrent chromosomal abnormalities and gene mutations detected at the time of diagnosis of acute myeloid leukemia (AML) are associated with particular disease features, treatment response and survival of AML patients, and are used to denote specific disease entities in the World Health Organization classification of myeloid neoplasms and acute leukemia. However, large studies that integrate cytogenetic and comprehensive mutational information are scarce. We created a comprehensive oncoprint of mutations associated with recurrent cytogenetic findings by combining the information on mutational patterns of 80 cancer- and leukemia-associated genes with cytogenetic findings in 1603 adult patients with de novo AML. We show unique differences in the mutational profiles among major cytogenetic subsets, identify novel associations between recurrent cytogenetic abnormalities and both specific gene mutations and gene functional groups, and reveal differences in cytogenetic and mutational features between patients younger than 60 years and those aged 60 years or older. The identified associations between cytogenetic and molecular genetic data may help guide mutation testing in AML, and result in more focused application of targeted therapy in patients with de novo AML.

  6. Importance of CD117 in the Assignation of a Myeloid Lineage in Acute Leukemias.

    Science.gov (United States)

    Pomerantz, Alan; Rodríguez-Rodríguez, Sergio; Demichelis-Gómez, Roberta; Barrera-Lumbreras, Georgina; Barrales-Benítez, Olga V; Díaz-Huízar, María José; Goldberg-Murow, Monica; López-Karpovitch, Xavier; Aguayo, Álvaro

    2017-02-01

    The correct classification of acute leukemias (AL) is an essential part in the evaluation of any patient with this disease. Historically, CD117 has been an important asset in the diagnosis of patients with mixed-phenotype acute leukemia (MPAL). In an attempt to simplify the diagnosis of MPAL with fewer and more lineage specific markers, the World Health Organization (WHO) proposed in 2008 a new criteria for the diagnosis of this type of AL, which excluded CD117 from the myeloid markers that are utilized to diagnose MPAL. In order to assess whether CD117 is necessary in the diagnosis of MPAL, we evaluated the sensitivity and specificity of CD117 for acute myeloid leukemia (AML) in 331 patients with AL. The calculated sensitivity of CD117 for AML was 85.88% (103/120), while the specificity was 83.9% (177/211). Besides myeloperoxidase (MPO), which was used as the gold standard in differentiating AML from other type of ALs, the most specific markers for AML in our study were CD14 and CD64 (99.5 and 95.6%). Although the specificity of CD117 in this study is not as high as CD14 and CD64, markers concomitantly used in this this study and in the WHO classification, based on the results of other researches (i.e. the specificity of CD117 for AML was 100% in one study) and due to the fact that its specificity for AML in this study is relatively high, we recommend the use CD117 in assigning a myeloid lineage in MPAL. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  7. Trisomy 8 in Pediatric Acute Myeloid Leukemia. A NOPHO-AML Study

    DEFF Research Database (Denmark)

    Laursen, Anne Cathrine Lund; Sandahl, Julie Damgaard; Kjeldsen, Eigil

    2016-01-01

    Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML......;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML...

  8. DNMT3A GENE POINT MUTATIONS DETECTION IN ACUTE MYELOID LEUKEMIA PATIENTS USING SEQUENCING TECHNIQUE

    OpenAIRE

    A. V. Vinogradov; A. V. Rezaykin; A. G. Sergeev

    2015-01-01

    Aim: to estimate the frequency of DNMT3A gene exons 18–26 point mutations in acute myeloid leukemia (AML) patients (pts) using target automatic sequencing technique.Material and Methods. Bone marrow and peripheral blood samples were obtained from 34 AML pts aged 21 to 64, who were treated in Sverdlovsk Regional Hematological Centre (Ekaterinburg) during the period 2012–2014. Distribution of the pts according to FAB-classification was as follows: AML M0 – 3, M1 – 1, M2 – 12, M3 – 3, M4 – 10, M...

  9. Rhabdomyolysis Caused by Candida parapsilosis in a Patient with Acute Myeloid Leukemia after Bone Marrow Transplantation.

    Science.gov (United States)

    Kakiuchi, Seiji; Yakushijin, Kimikazu; Yamamoto, Katsuya; Tomioka, Hideo; Inui, Yumiko; Okamura, Atsuo; Kawamoto, Shinichiro; Minami, Yosuke; Murayama, Tohru; Ito, Mitsuhiro; Matsuoka, Hiroshi; Minami, Hironobu

    2015-01-01

    Rhabdomyolysis is characterized by a marked elevation of the creatine kinase (CK) levels and myoglobinuria, thus leading to renal dysfunction. Various viruses or bacteria can be etiologic agents, but mycosis has only rarely been reported to be a cause of rhabdomyolysis. In this report, we describe an adolescent male with acute myeloid leukemia who underwent allogeneic bone marrow transplantation and thereafter developed rhabdomyolysis and Candida parapsilosis fungemia almost at the same time. Following treatment for C. parapsilosis, the transaminase and CK levels both satisfactorily decreased. This case illustrates that C. parapsilosis infection may be a causative agent of rhabdomyolysis in immunocompromised patients.

  10. Stepwise discriminant function analysis for rapid identification of acute promyelocytic leukemia from acute myeloid leukemia with multiparameter flow cytometry.

    Science.gov (United States)

    Chen, Zhanguo; Li, Yan; Tong, Yongqing; Gao, Qingping; Mao, Xiaolu; Zhang, Wenjing; Xia, Zunen; Fu, Chaohong

    2016-03-01

    Diagnosis of acute promyelocytic leukemia (APL) has been accelerated by multiparameter flow cytometry (MFC). However, diagnostic interpretation of MFC readouts for APL depends on individual experience and knowledge, which inevitably increases the risk of arbitrariness. We appraised the feasibility of using stepwise discriminant function analysis (SDFA) based on MFC to optimize the minimal variables needed to distinguish APL from other acute myeloid leukemia (AML) without complicated data interpretation. Samples from 327 patients with APL (n = 51) and non-APL AML (n = 276) were randomly allocated into training (243 AML) and test sets (84 AML) for SDFA. The discriminant functions from SDFA were examined by correct classification, and the final variables were validated by differential expression. Finally, additional 20 samples from patients with atypical APL and AML confusable with APL were also identified by SDFA method and morphological analysis. The weighed discriminant function reveals seven differentially expressed variables (CD2/CD9/CD11b/CD13/CD34/HLA-DR/CD117), which predict a molecular result for APL characterization with an accuracy that approaches 99% (99.6 and 98.8% for AML samples in training and test sets, respectively). Furthermore, the SDFA outperformed either single variable analysis or the more limited 3-component analysis (CD34/CD117/HLA-DR) via separate SDFA, and was also superior to morphological analysis in terms of diagnostic efficacy. The established SDFA based on MFC with seven variables can precisely and rapidly differentiate APL and non-APL AML, which may contribute to the urgent initiation of all-trans-retinoic acid-based APL therapy.

  11. Biological and clinical meaning of myeloid antigen expression in the acute lymphocytic leukemia in children

    International Nuclear Information System (INIS)

    Marsan Suarez, Vianed; Sanchez Segura, Miriam; Socarras Ferrer, Bertha B; Valle Perez, Lazaro O del

    2009-01-01

    In 238 children presenting with acute lymphoid leukemia (ALL) authors studied the possible association between the myeloid antigens expression with determined biologic and clinic features at disease onset. The cellular immunophenotyping was performed by ultraimmunocytochemical method. From the total of diagnosed ALLs, the 21,8% were LLA-Mi+. There was a lymphadenopathies predominance (71,2%), splenomegaly (65,4%) and hepatomegaly (57,7%) in patients with LLA-Mi+ and very significant differences (p =0,003, p = 0,0068, and p = 0,000, respectively. There was also alight predominance of mediastinum adenopathies, CNS infiltration and hemorrahagic manifestations in patients with LLA-Mi+, no statistically significant. Results showed that in our patients the myeloid antigen expression on the lymphoid blasts influenced on appearance of determined presentation of morphologic and clinical features in children

  12. PROGNOSTIC VALUE OF BRAIN AND ACUTE LEUKEMIA CYTOPLASMIC GENE EXPRESSION IN EGYPTIAN CHILDREN WITH ACUTE MYELOID LEUKEMIA

    Directory of Open Access Journals (Sweden)

    adel abd elhaleim hagag

    2015-04-01

    Full Text Available Abstract      Background: Acute myeloid leukemia (AML accounts for 25%-35% of the acute leukemia in children. BAALC (Brain and Acute Leukemia, Cytoplasmic gene is a recently identified gene on chromosome 8q22.3 that has prognostic significance in AML.  The aim of this work was to study the impact of BAALC gene expression on prognosis of AML in Egyptian children. Patients and methods: This study was conducted on 40 patients of newly diagnosed AML who were subjected to the following: Full history taking, clinical examination, laboratory investigations including: complete blood count, LDH, bone marrow aspiration, cytochemistry and immunophenotyping, assessment of BAALC Gene by real time PCR in bone marrow aspirate mononuclear cells before the start of chemotherapy. Results: BAALC gene expression showed positive expression in 24 cases (60% and negative expression in 16 cases (40%. Patients who showed positive BAALC gene expression included 10 patients achieved complete remission, 8 patients died and 6 relapsed patients, while patients who showed negative expression include 12 patients achieved complete remission, 1 relapsed patient and 3 patients died. There was significant association between BAALC gene expression and FAB classification of patients of AML patientsas positive BAALC expression is predominantly seen in FAB subtypes M1 and M2 compared with negative BAALC gene expression that was found more in M3 and M4 (8 cases with M1, 12 cases with M2, 1 case with M3 and 3 cases with M4 in positive BAALC expression versus 2 cases with M1, 3 cases with M2, 4 cases with M3 and 7 cases with M4 in BAALC gene negative expression group with significant difference regarding FAB subtypes. As regard age, sex, splenomegaly, lymphadenopathy, pallor, purpura, platelets count, WBCs count, and percentage of blast cells in BM, the present study showed no significant association with BAALC. Conclusion: BAALC expression is an important prognostic factor in AML

  13. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia.

    Science.gov (United States)

    Placke, Theresa; Faber, Katrin; Nonami, Atsushi; Putwain, Sarah L; Salih, Helmut R; Heidel, Florian H; Krämer, Alwin; Root, David E; Barbie, David A; Krivtsov, Andrei V; Armstrong, Scott A; Hahn, William C; Huntly, Brian J; Sykes, Stephen M; Milsom, Michael D; Scholl, Claudia; Fröhling, Stefan

    2014-07-03

    Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts. © 2014 by The American Society of Hematology.

  14. A case of acute myeloid leukemia with e6a2 BCR-ABL fusion transcript acquired after progressing from chronic myelomonocytic leukemia

    OpenAIRE

    Jinjuan Yao; Dan Douer; Lu Wang; Maria E. Arcila; Khedoudja Nafa; April Chiu

    2017-01-01

    Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myeloid leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while a small subset of the cases expresses e1a2 or e19a2 transcripts. We report a patient with chronic myelomonocytic leukemia (CMML), initially Ph chromosome negative at presentation, with rapid disease progression to acute myeloid leukemia (AML) and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion trans...

  15. [Clinical and biological prognostic factors in relapsed acute myeloid leukemia patients].

    Science.gov (United States)

    Yébenes-Ramírez, Manuel; Serrano, Josefina; Martínez-Losada, Carmen; Sánchez-García, Joaquín

    2016-09-02

    Acute myeloid leukemia (AML) is the most frequent type of acute leukemia in adults. Despite recent advances in the characterization of pathogenesis of AML, the cure rates are under 40%, being leukemia relapse the most common cause of treatment failure. Leukaemia relapse occurs due to clonal evolution or clonal escape. In this study, we aimed to analyze the clinical and biological factors influencing outcomes in patients with AML relapse. We included a total of 75 AML patients who experienced leukaemia relapse after achieving complete remission. We performed complete immunophenotyping and conventional karyotyping in bone marrow aspirates obtained at diagnosis and at leukemia relapse. Overall survival (OS) of the series was 3.7%±2.3, leukaemia progression being the most common cause of death. Patients relapsing before 12 months and those with adverse cytogenetic-molecular risk had statistically significant worse outcomes. A percentage of 52.5 of patients showed phenotypic changes and 50% cytogenetic changes at relapse. We did not find significant clinical factors predicting clonal evolution. The presence of clonal evolution at relapse did not have a significant impact on outcome. Patients with relapsed AML have a dismal prognosis, especially those with early relapse and adverse cytogenetic-molecular risk. Clonal evolution with phenotypic and cytogenetic changes occurred in half of the patients without predictive clinical factors or impact on outcome. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  16. Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: Impact on WHO classification.

    Science.gov (United States)

    Pasqualucci, Laura; Liso, Arcangelo; Martelli, Maria Paola; Bolli, Niccolò; Pacini, Roberta; Tabarrini, Alessia; Carini, Manola; Bigerna, Barbara; Pucciarini, Alessandra; Mannucci, Roberta; Nicoletti, Ildo; Tiacci, Enrico; Meloni, Giovanna; Specchia, Giorgina; Cantore, Nicola; Di Raimondo, Francesco; Pileri, Stefano; Mecucci, Cristina; Mandelli, Franco; Martelli, Massimo Fabrizio; Falini, Brunangelo

    2006-12-15

    Because of a lack of specific clonality markers, information on lineage involvement and cell of origin of acute myeloid leukemia with normal karyotype (AML-NK), is missing. Because Nucleophosmin (NPM) gene is frequently mutated in AML-NK and causes aberrant NPM cytoplasmic localization (NPMc+), it was used as an AML lineage clonality marker. Clonal NPM exon 12 mutations were detected in myeloid, monocytic, erythroid, and megakaryocytic cells but not in fibroblasts or endothelia that were laser-microdissected from 3 patients with NPMc+ AML. Aberrant cytoplasmic expression of mutated NPM proteins was identified with anti-NPM antibodies in 2 or more myeloid hemopoietic cell lineages in 99 (61.5%) of 161 of NPMc+ AML paraffin-embedded bone marrow biopsies; lymphoid involvement was excluded in 3 investigated cases. These findings suggest that NPMc+ AML derives from either a common myeloid or earlier progenitor. Immunohistochemical studies show that varying combinations and ratios of NPMc+ leukemic cells from distinct lineages are responsible for heterogeneity within each French-American-British (FAB) classification type and for NPMc+ AML falling into different FAB categories. These findings question the value of FAB criteria in subdividing the WHO category of "AML not otherwise characterized" and suggest that, for clinical use, NPMc+ AML be provisionally regarded as a separate AML with prognostic significance.

  17. Global proteomics dataset of miR-126 overexpression in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Erwin M. Schoof

    2016-12-01

    Full Text Available A deep proteomics analysis was conducted on a primary acute myeloid leukemia culture system to identify potential protein targets regulated by miR-126. Leukemia cells were transduced either with an empty control lentivirus or one containing the sequence for miR-126, and resulting cells were analyzed using ultra-high performance liquid chromatography (UHPLC coupled with high resolution mass spectrometry. The mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PRIDE: PXD001994. The proteomics data and statistical analysis described in this article is associated with a research article, “miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells” (Lechman et al., 2016 [1], and serves as a resource for researchers working in the field of microRNAs and their regulation of protein levels.

  18. Association between MTHFR polymorphisms and acute myeloid leukemia risk: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Yu-Tao Qin

    Full Text Available Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR polymorphisms and acute myeloid leukemia risk (AML have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs with 95% confidence intervals (CIs were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls and 9 studies (1335 patients and 4295 controls for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98-1.04; 95% CI, 0.86-0.92 to 1.09-1.25. Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis.

  19. Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis

    Science.gov (United States)

    Su, Yan; Lu, Ge-Ning; Wang, Ren-Sheng

    2014-01-01

    Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and acute myeloid leukemia risk (AML) have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C) polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls) and 9 studies (1335 patients and 4295 controls) for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98–1.04; 95% CI, 0.86–0.92 to 1.09–1.25). Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis. PMID:24586405

  20. Extramedullary Acute Myeloid Leukemia (AML: Leukemic Pleural Effusion, Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Naveen ePemmaraju

    2014-06-01

    Full Text Available Objective and Importance: Malignant pleural effusions occur in the setting of both solid and hematologic malignancies. Pleural effusion caused by leukemic infiltration is an unusual extramedullary manifestation of acute myeloid leukemia (AML with fewer than 20 cases reported.1-11 We report a case of pericardial and pleural effusions in a patient with AML and review the literature. Clinical presentation: In this case, a 55 year old man with previous history of myeloproliferative neoplasm (MPN experienced transformation AML, heralded by appearance of leukemic pleural effusions. The patient was identified to have leukemic pleural effusion based upon extended cytogenetic analysis of the pleural fluid, as morphologic analysis alone was insufficient. Intervention: The patient was treated with hypomethylator-based and intensive chemotherapy strategies, both of which maintained resolution of the effusions in the remission setting. Conclusion: Due to the rarity of diagnosis of leukemic pleural effusions, both cytogenetic and fluorescence in situ hybridization (FISH testing are recommended. Futhermore, systemic chemotherapy directed at the AML can lead to complete resolution of leukemic pleural effusions. Objective and ImportancePleural effusion caused by leukemic infiltration is an unusual extramedullary manifestation of acute myeloid leukemia (AML, but may be more common than previously thought. Fewer than 20 cases have been reported.1-11 We report a case of pericardial and pleural effusions in a patient with AML and review the literature.

  1. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

    Science.gov (United States)

    Arber, Daniel A; Orazi, Attilio; Hasserjian, Robert; Thiele, Jürgen; Borowitz, Michael J; Le Beau, Michelle M; Bloomfield, Clara D; Cazzola, Mario; Vardiman, James W

    2016-05-19

    The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here. © 2016 by The American Society of Hematology.

  2. A phase II study of the EGFR inhibitor gefitinib in patients with acute myeloid leukemia.

    Science.gov (United States)

    Deangelo, Daniel J; Neuberg, Donna; Amrein, Philip C; Berchuck, Jacob; Wadleigh, Martha; Sirulnik, L Andres; Galinsky, Ilene; Golub, Todd; Stegmaier, Kimberly; Stone, Richard M

    2014-04-01

    Novel therapies for the treatment of acute myeloid leukemia are required to overcome disease resistance and to provide potentially less toxic therapies for older adults. Prior clinical trials involving patients with non-small cell lung cancer have demonstrated the safety and biologic activity of the administration of EGFR inhibitors in carefully selected patients. The potential efficacy of this approach in patients with acute myeloid leukemia is unknown. The effects of gefitinib on differentiation induction and cell viability in AML cell lines and primary patient AML cells were previously reported and cell viability was inhibited in a clinically achievable range. To determine if EGFR inhibitors would be therapeutically efficacious in advanced AML, we performed a phase II trial in which 18 patients with a median age of 72 (range, 57-84 years) were treated with gefitinib (750mg orally daily). While there were no unexpected toxicities, no patients experienced an objective response, though one had stable disease lasting 16 months. We conclude that in spite of pre-clinical activity and anecdotal cases of response to EGFR inhibitors, routine use of the EGFR inhibitor gefitinib as a single agent for advanced AML is not appropriate. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Acute myeloid leukemia after kidney transplantation: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Francesca Cardarelli

    Full Text Available Abstract The incidence of malignancy is greater in kidney transplant recipients compared to the general population, though the higher risk is not equally distributed to all types of cancers. In face of the increased longevity of renal transplant recipients, certain cancers, such as acute leukemias, are becoming more prevalent. Acute myeloid leukemia (AML typically presents with cytopenias and infections, both common findings after kidney transplantation. Therefore, the diagnosis of AML may be initially overlooked in these patients. We report the case of a 33-year-old man who presented with fever, pancytopenia and acute worsening of his renal allograft function 9 years after a living unrelated kidney transplant. After initial negative infectious work-up, a kidney biopsy revealed C4d-positive antibody-mediated rejection in combination with scattered atypical inflammatory cells. A subsequent bone marrow biopsy confirmed AML. He underwent successful induction chemotherapy with daunorubucin and cytarabine and ultimately achieved a complete remission. However, he developed a Page kidney with worsening renal function and abdominal pain three weeks after biopsy in the setting of chemotherapy-induced thrombocytopenia. Herein, we discuss the prevalence, risk factors, presentation and management of leukemia after kidney transplantation.

  4. BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features.

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    Neuendorff, Nina Rosa; Burmeister, Thomas; Dörken, Bernd; Westermann, Jörg

    2016-08-01

    BCR-ABL-positive acute myeloid leukemia (AML) is a rare subtype of AML that is now included as a provisional entity in the 2016 revised WHO classification of myeloid malignancies. Since a clear distinction between de novo BCR-ABL+ AML and chronic myeloid leukemia (CML) blast crisis is challenging in many cases, the existence of de novo BCR-ABL+ AML has been a matter of debate for a long time. However, there is increasing evidence suggesting that BCR-ABL+ AML is in fact a distinct subgroup of AML. In this study, we analyzed all published cases since 1975 as well as cases from our institution in order to present common clinical and molecular features of this rare disease. Our analysis shows that BCR-ABL predominantly occurs in AML-NOS, CBF leukemia, and AML with myelodysplasia-related changes. The most common BCR-ABL transcripts (p190 and p210) are nearly equally distributed. Based on the analysis of published data, we provide a clinical algorithm for the initial differential diagnosis of BCR-ABL+ AML. The prognosis of BCR-ABL+ AML seems to depend on the cytogenetic and/or molecular background rather than on BCR-ABL itself. A therapy with tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinib is reasonable, but-due to a lack of systematic clinical data-their use cannot be routinely recommended in first-line therapy. Beyond first-line treatment of AML, the use of TKI remains an individual decision, both in combination with intensive chemotherapy and/or as a bridge to allogeneic stem cell transplantation. In each single case, potential benefits have to be weighed against potential risks.

  5. Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia.

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    Tao, Yan-Fang; Fang, Fang; Hu, Shao-Yan; Lu, Jun; Cao, Lan; Zhao, Wen-Li; Xiao, Pei-Fang; Li, Zhi-Heng; Wang, Na-Na; Xu, Li-Xiao; Du, Xiao-Juan; Sun, Li-Chao; Li, Yan-Hong; Li, Yi-Ping; Xu, Yun-Yun; Ni, Jian; Wang, Jian; Feng, Xing; Pan, Jian

    2015-10-21

    Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature of AML. GATA4 has been suggested to be a tumor suppressor gene regulated by promoter hypermethylation in various types of human cancers although the expression and promoter methylation of GATA4 in pediatric AML is still unclear. Transcriptional expression levels of GATA4 were evaluated by semi-quantitative and real-time PCR. Methylation status was investigated by methylation-specific PCR (MSP) and bisulfate genomic sequencing (BGS). The prognostic significance of GATA4 expression and promoter methylation was assessed in 105 cases of Chinese pediatric acute myeloid leukemia patients with clinical follow-up records. MSP and BGS analysis showed that the GATA4 gene promoter is hypermethylated in AML cells, such as the HL-60 and MV4-11 human myeloid leukemia cell lines. 5-Aza treatment significantly upregulated GATA4 expression in HL-60 and MV4-11 cells. Aberrant methylation of GATA4 was observed in 15.0 % (3/20) of the normal bone marrow control samples compared to 56.2 % (59/105) of the pediatric AML samples. GATA4 transcript levels were significantly decreased in AML patients (33.06 ± 70.94; P = 0.011) compared to normal bone marrow/idiopathic thrombocytopenic purpura controls (116.76 ± 105.39). GATA4 promoter methylation was correlated with patient leukocyte counts (WBC, white blood cells) (P = 0.035) and minimal residual disease MRD (P = 0.031). Kaplan-Meier survival analysis revealed significantly shorter overall survival time in patients with GATA4 promoter methylation (P = 0.014). Epigenetic inactivation of GATA4 by promoter hypermethylation was observed in both AML cell lines and pediatric AML samples; our study implicates GATA4 as a putative tumor suppressor gene in pediatric AML. In addition, our findings imply that GATA4 promoter methylation is correlated with WBC and MRD. Kaplan

  6. Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia

    International Nuclear Information System (INIS)

    Tao, Yan-Fang; Fang, Fang; Hu, Shao-Yan; Lu, Jun; Cao, Lan; Zhao, Wen-Li; Xiao, Pei-Fang; Li, Zhi-Heng; Wang, Na-Na; Xu, Li-Xiao; Du, Xiao-Juan; Sun, Li-Chao; Li, Yan-Hong; Li, Yi-Ping; Xu, Yun-Yun; Ni, Jian; Wang, Jian; Feng, Xing; Pan, Jian

    2015-01-01

    Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature of AML. GATA4 has been suggested to be a tumor suppressor gene regulated by promoter hypermethylation in various types of human cancers although the expression and promoter methylation of GATA4 in pediatric AML is still unclear. Transcriptional expression levels of GATA4 were evaluated by semi-quantitative and real-time PCR. Methylation status was investigated by methylation-specific PCR (MSP) and bisulfate genomic sequencing (BGS). The prognostic significance of GATA4 expression and promoter methylation was assessed in 105 cases of Chinese pediatric acute myeloid leukemia patients with clinical follow-up records. MSP and BGS analysis showed that the GATA4 gene promoter is hypermethylated in AML cells, such as the HL-60 and MV4-11 human myeloid leukemia cell lines. 5-Aza treatment significantly upregulated GATA4 expression in HL-60 and MV4-11 cells. Aberrant methylation of GATA4 was observed in 15.0 % (3/20) of the normal bone marrow control samples compared to 56.2 % (59/105) of the pediatric AML samples. GATA4 transcript levels were significantly decreased in AML patients (33.06 ± 70.94; P = 0.011) compared to normal bone marrow/idiopathic thrombocytopenic purpura controls (116.76 ± 105.39). GATA4 promoter methylation was correlated with patient leukocyte counts (WBC, white blood cells) (P = 0.035) and minimal residual disease MRD (P = 0.031). Kaplan-Meier survival analysis revealed significantly shorter overall survival time in patients with GATA4 promoter methylation (P = 0.014). Epigenetic inactivation of GATA4 by promoter hypermethylation was observed in both AML cell lines and pediatric AML samples; our study implicates GATA4 as a putative tumor suppressor gene in pediatric AML. In addition, our findings imply that GATA4 promoter methylation is correlated with WBC and MRD. Kaplan-Meier survival analysis

  7. Lymphoid associated antigen expression in new cases of Acute Myeloid Leukemia

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    R Jha

    2013-10-01

    Full Text Available Background: Occurrence of aberrant phenotype has been reported in acute leukemias with varying frequency though its prognostic importance remains controversial. In acute myeloid leukemias, aberrant phenotype, as high as 88 %, has been reported. To evaluate the occurrence of aberrant lymphoid phenotypes and to correlate their presence with various French American British classification, 100 cases of fresh acute myeloid leukemias were analyzed for lymphoid markers CD 4,7,8,10 and 19. Materials and Methods: Whole blood or bone marrow aspirate collected in EDTA were processed by standard method and subjected to immunophenotyping for B Cells marker CD 19 and 10 and T cell marker CD 4, 7 and 8. Results: Aberrant lymphoid markers were seen in 35(35% cases. All FAB subtypes except M7 showed aberrancy for the markers studied. However it was the most common in M0 (100%, followed by M2 (51.9%. T cell aberrancy was the most common, comprising 62.8% (22/35 of total aberrancy. CD 7 was the most common aberrantly expressed marker, seen in 20% AML, followed by CD 4(14% and CD 19 (8%. Conclusion: Occurrence of lymphoid phenotypes is frequent in pediatric as well adult AML. Though T cell markers are more common, only B cell as well as both B and T cell markers may be co expressed. DOI: http://dx.doi.org/10.3126/jpn.v3i6.8999   Journal of Pathology of Nepal (2013 Vol. 3, 487-490

  8. Bioelectrical Impedance Measurement for Predicting Treatment Outcome in Patients With Newly Diagnosed Acute Leukemia

    Science.gov (United States)

    2018-01-24

    Acute Undifferentiated Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Mast Cell Leukemia; Myeloid/NK-cell Acute Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  9. Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival.

    Science.gov (United States)

    Kornblau, Steven M; Ruvolo, Peter P; Wang, Rui-Yu; Battula, V Lokesh; Shpall, Elisabeth J; Ruvolo, Vivian R; McQueen, Teresa; Qui, YiHua; Zeng, Zhihong; Pierce, Sherry; Jacamo, Rodrigo; Yoo, Suk-Young; Le, Phuong M; Sun, Jeffery; Hail, Numsen; Konopleva, Marina; Andreeff, Michael

    2018-03-15

    Mesenchymal stromal cells support acute myeloid leukemia cell survival in the bone marrow microenvironment. Protein expression profiles of acute myeloid leukemia-derived mesenchymal stromal cells are unknown. Reverse phase protein array analysis was performed to compare expression of 151 proteins from acute myeloid leukemia mesenchymal stromal cells (n = 106) with mesenchymal stromal cells from healthy donors (n = 71). Protein expression differed significantly between the two groups with nineteen proteins overexpressed in leukemia stromal cells and nine overexpressed in normal stromal cells. Unbiased hierarchical clustering analysis of the samples using these twenty-eight proteins revealed three protein constellations whose variation in expression defined four mesenchymal stromal cells protein expression signatures: Class 1, Class 2, Class 3, and Class 4. These cells populations appear to have clinical relevance. Specifically, patients with Class 3 cells have longer survival and remission duration compared to other groups. Comparison of leukemia mesenchymal stromal cells at first diagnosis with those obtained at salvage (i.e., relapse/refractory) showed differential expression of nine proteins reflecting a shift toward osteogenic differentiation. Leukemia mesenchymal stromal cells are more senescent compared to their normal counterparts, possibly due to the over expressed p53/p21 axis as confirmed by high β-galactosidase staining. In addition, over expression of BCL-XL in leukemia mesenchymal stromal cells might accord survival advantage under conditions of senescence or stress and over-expressed galectin-3 exerts profound immunosuppression. Together, our findings suggest that the identification of specific populations of mesenchymal stromal cells in acute myeloid leukemia patients may be an important determinant of therapeutic response. Copyright © 2018, Ferrata Storti Foundation.

  10. A mind map for managing minimal residual disease in acute myeloid leukemia.

    Science.gov (United States)

    Benton, Christopher B; Ravandi, Farhad

    2017-11-01

    Advances in detecting traces of leukemia that were previously unidentifiable have increasingly led to the incorporation of information about residual disease into clinical decision making for patients with leukemia in both the postinduction and consolidation settings. This review discusses current concepts related to minimal residual disease (MRD), which is defined as submicroscopic disease detected during morphologic complete remission. The focus is on acute myeloid leukemia (AML). Basic methods for detecting MRD include flow cytometry, reverse transcription-polymerase chain reaction, and mutation analysis. Several studies using these assays have demonstrated prognostic implications based on MRD-positive vs MRD-negative status. As our understanding of the biological factors responsible for MRD in AML evolves, residual disease should be evaluated in the context of other prognostic markers. Current therapeutic options for managing MRD in AML are limited, and the clinical implications of a positive MRD test result can be significant. Regarding individual patients, an evidence-based approach must be applied while the institution- and assay-specific differences that currently exist are considered. Challenges associated with MRD assessment, such as the limited standardization of available assays and the paucity of effective agents to eradicate MRD, will need to be overcome before physicians who treat leukemia can use MRD as a tool for clinical management.

  11. Occurrence of Acute Myeloid Leukemia in Young Pregnant Women

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    Juliane Menezes

    2008-01-01

    Full Text Available Although acute leukaemia is rare in pregnancy its importance lies in its life-threatening potential, both to the child and the mother. The possibility of vertical transmission of leukemic cells increases the attention devoted to these patients and their offspring. Three cases of pregnant young women (15-17 years of age with AML are presented. This series of cases is the first report where gene abnormalities such as ITD mutations of the FLT3 gene and AML1/ETO fusion genes were screened in pregnant AML patients and their babies, so far. Unfortunately, very poor outcomes have been associated to similar cases described in literature, and the same was true to the patients described herein. Although very speculative, we think that the timing and possible similar exposures would be involved in all cases.

  12. Alloreactive natural killer cells for the treatment of acute myeloid leukemia: from stem cell transplantation to adoptive immunotherapy

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    Loredana eRuggeri

    2015-10-01

    Full Text Available Natural killer cells express activating and inhibitory receptors which recognize MHC class I alleles, termed Killer cell Immunoglobulin-like Receptors (KIRs. Preclinical and clinical data from haploidentical T-cell depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched natural killer cells play a major role as effectors against acute myeloid leukemia. Outside the transplantation setting, several reports have proven the safety and feasibility of natural killer cell infusion in acute myeloid leukemia patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. Aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts of exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against acute myeloid leukemia. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of acute myeloid leukemia.

  13. Differences between the CD34+ and CD34- blast compartments in apoptosis resistance in acute myeloid leukemia.

    NARCIS (Netherlands)

    Stijn, van A.; Pol, van der M.A.; Kok, A.; Bontje, PM; Roemen, GM; Beelen, R.H.J.; Ossenkoppele, G.J.; Schuurhuis, G.J.

    2003-01-01

    BACKGROUND AND OBJECTIVES: Altered expression of members of the Bcl-2 family might account for the observed apoptosis resistance to chemotherapy in acute myeloid leukemia (AML). Given the poor prognosis associated with CD34+ expression in AML, we studied the role of spontaneous apoptosis and

  14. P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia

    NARCIS (Netherlands)

    de Vries, EGE; van Putten, WLJ; Verdonck, LF; Ossenkoppele, GJ; Verhoef, GEG; Vellenga, E

    Despite treatment with intensive chemotherapy, a considerable number of patients with acute myeloid leukemia (AML) die from their disease due to the occurrence of resistance. Overexpression of the transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP) 1 has been identified

  15. Cytomegalovirus induces HLA-class-II-restricted alloreactivity in an acute myeloid leukemia cell line.

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    Michael Koldehoff

    Full Text Available Cytomegalovirus (HCMV reactivation is found frequently after allogeneic hematopoietic stem cell transplantation (alloSCT and is associated with an increased treatment-related mortality. Recent reports suggest a link between HCMV and a reduced risk of cancer progression in patients with acute leukemia or lymphoma after alloSCT. Here we show that HCMV can inhibit the proliferation of the acute myeloid leukemia cell line Kasumi-1 and the promyeloid leukemia cell line NB4. HCMV induced a significant up-regulation of HLA-class-II-molecules, especially HLA-DR expression and an increase of apoptosis, granzyme B, perforin and IFN-γ secretion in Kasumi-1 cells cocultured with peripheral blood mononuclear cells (PBMCs. Indolamin-2,3-dioxygenase on the other hand led only to a significant dose-dependent effect on IFN-γ secretion without effects on proliferation. The addition of CpG-rich oligonucleotides and ganciclovir reversed those antiproliferative effects. We conclude that HCMV can enhance alloreactivity of PBMCs against Kasumi-1 and NB4 cells in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required.

  16. Extensive Bone Marrow Necrosis in a Case of Acute Myeloid Leukemia Transformed from a Myeloproliferative Neoplasm

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    Roman Shapiro

    2015-08-01

    Full Text Available Extensive necrosis affecting more than 50% of the bone marrow is an extremely rare histopathological finding. Relatively little is known about its clinical significance because it is most commonly identified at autopsy - whether it is an independent prognostic marker or whether it is a surrogate marker of underlying disease burden remains unclear. We describe herein a case of a 66-year-old patient with acute myeloid leukemia who presented with acute bone marrow failure and was found to have extensive necrosis. We include presenting clinical features, pathology attained at biopsy, and the challenge of treatment. Bone marrow necrosis is a rare but important clinicopathological entity whose recognition may herald the way for more effective prognostication of underlying disease.

  17. Nilotinib-Induced Acute Pancreatitis in a Patient with Chronic Myeloid Leukemia

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    Vihang Patel

    2017-05-01

    Full Text Available Nilotinib, a second-generation tyrosine kinase inhibitor, is used for treatment of chronic myeloid leukemia (CML; it has been widely used especially for imatinib-resistant CML. Despite being a novel drug in this therapeutic class, it has the potential to be harmful. We present the case of an elderly woman who developed life-threatening acute pancreatitis as an adverse event after having started the drug. There is only one reported case in the literature of nilotinib-induced acute pancreatitis. The purpose of this case report is to educate physicians who prescribe this medication to be aware of potential life-threatening adverse events. As more and more therapies are available, physicians should be aware of potential effects of cancer treatment that could be life-threatening to patients.

  18. Dasatinib accelerates valproic acid-induced acute myeloid leukemia cell death by regulation of differentiation capacity.

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    Sook-Kyoung Heo

    Full Text Available Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.

  19. Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells.

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    Sook-Kyoung Heo

    Full Text Available Radotinib, developed as a BCR/ABL tyrosine kinase inhibitor (TKI, is approved for the second-line treatment of chronic myeloid leukemia (CML in South Korea. However, therapeutic effects of radotinib in acute myeloid leukemia (AML are unknown. In the present study, we demonstrate that radotinib significantly decreases the viability of AML cells in a dose-dependent manner. Kasumi-1 cells were more sensitive to radotinib than NB4, HL60, or THP-1 cell lines. Furthermore, radotinib induced CD11b expression in NB4, THP-1, and Kasumi-1 cells either in presence or absence of all trans-retinoic acid (ATRA. We found that radotinib promoted differentiation and induced CD11b expression in AML cells by downregulating LYN. However, CD11b expression induced by ATRA in HL60 cells was decreased by radotinib through upregulation of LYN. Furthermore, radotinib mainly induced apoptosis of CD11b+ cells in the total population of AML cells. Radotinib also increased apoptosis of CD11b+ HL60 cells when they were differentiated by ATRA/dasatinib treatment. We show that radotinib induced apoptosis via caspase-3 activation and the loss of mitochondrial membrane potential (ΔΨm in CD11b+ cells differentiated from AML cells. Our results suggest that radotinib may be used as a candidate drug in AML or a chemosensitizer for treatment of AML by other therapeutics.

  20. A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

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    Konstantinos Tzelepis

    2016-10-01

    Full Text Available Acute myeloid leukemia (AML is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.

  1. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications.

    Science.gov (United States)

    Sportoletti, P; Varasano, E; Rossi, R; Mupo, A; Tiacci, E; Vassiliou, G; Martelli, M P; Falini, B

    2015-02-01

    Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) mutations displays distinct biological and clinical features that led to its inclusion as a provisional disease entity in the 2008 World Health Organization (WHO) classification of myeloid neoplasms. Studies of the molecular mechanisms underlying the pathogenesis of NPM1-mutated AML have benefited greatly from several mouse models of this leukemia developed over the past few years. Immunocompromised mice xenografted with NPM1-mutated AML served as the first valuable tool for defining the biology of the disease in vivo. Subsequently, genetically engineered mouse models of the NPM1 mutation, including transgenic and knock-in alleles, allowed the generation of mice with a constant genotype and a reproducible phenotype. These models have been critical for investigating the nature of the molecular effects of these mutations, defining the function of leukemic stem cells in NPM1-mutated AML, identifying chemoresistant preleukemic hemopoietic stem cells and unraveling the key molecular events that cooperate with NPM1 mutations to induce AML in vivo. Moreover, they can serve as a platform for the discovery and validation of new antileukemic drugs in vivo. Advances derived from the analysis of these mouse models promise to greatly accelerate the development of new molecularly targeted therapies for patients with NPM1-mutated AML.

  2. Therapeutic reactivation of protein phosphatase 2A in acute myeloid leukemia

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    Kavitha eRamaswamy

    2015-02-01

    Full Text Available Protein phosphatase 2A (PP2A is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML. By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re-activation: i allosteric activation of the phosphatase activity, and ii stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation.

  3. In vitro evaluation of triazenes: DNA cleavage, antibacterial activity and cytotoxicity against acute myeloid leukemia cells

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    Domingues, Vanessa O.; Hoerner, Rosmari; Reetz, Luiz G.B.; Kuhn, Fabio, E-mail: rosmari.ufsm@gmail.co [Universidade Federal de Santa Maria (UFSM), RS (Brazil). Dept. de Analises Clinicas e Toxicologicas; Coser, Virginia M.; Rodrigues, Jacqueline N.; Bauchspiess, Rita; Pereira, Waldir V. [Hospital Universitario de Santa Maria, RS (Brazil). Dept. de Hematologia-Oncologia; Paraginski, Gustavo L.; Locatelli, Aline; Fank, Juliana de O.; Giglio, Vinicius F.; Hoerner, Manfredo, E-mail: hoerner.manfredo@gmail.co [Universidade Federal de Santa Maria (UFSM), RS (Brazil). Dept. de Quimica

    2010-07-01

    The asymmetric diazoamines 1-(2-chlorophenyl)-3-(4-carboxyphenyl)triazene (1), 1-(2-fluorophenyl)-3-(4-carboxyphenyl)triazene (2) and 1-(2-fluorophenyl)-3-(4-amidophenyl) triazene (3) were evaluated for their ability to cleave pUC18 and pBSKII plasmid DNA, antibacterial activity and in vitro cytotoxicity against acute myeloid leukemia cells and normal leukocytes using the bioassay of reduction of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The triazenes showed ability to cleave the two types of plasmid DNA: triazene 1 at pH 8.0 and 50 deg C; triazene 2 at pH 6.5 and 37 and 50 deg C; triazene 3 at pH 6.5 and 37 deg C. The compounds presented cytotoxic activity against myeloid leukemia cells. Compound 1 showed high activity against B. cereus (MIC = 32 {mu}g mL{sup -1}). The observation of intermolecular hydrogen bonding in the solid state of compound 3, based on the structural analysis by X-ray crystallography, as well as the results of IR and UV-Vis spectroscopic analyses of compounds 1, 2 and 3 are discussed in the present work. (author)

  4. The Past, Present and Future Subclassification of Patients with Acute Myeloid Leukemia.

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    Forthun, Rakel B; Hinrichs, Carina; Dowling, Tara H; Bruserud, Øystein; Selheim, Frode

    2016-01-01

    Acute myeloid leukemia (AML) is characterized as a heterogeneous disease where the patients are sub grouped according to several classification systems and mutational analyses. Diagnosis of AML is based on identification of the specific myeloid cell initiating the disease, quantification of immature blasts in bone marrow and peripheral blood, as well as detection of mutations and translocations. The heterogeneity of AML is caused by a block in differentiation that may occur in any of the different myeloid cell populations. These undifferentiated cells also harbor an increased proliferation potential that leads to accumulation of immature leukemic cells. The current development of more sensitive and less labor intensive analysis methods has led classification of patients from being a system based on morphology of the leukemic cells to being more sophisticated, detecting translocations and small mutations found in the whole leukemic clone or in a minor subclone. This review aims to describe the most common classification systems of AML, including frequently occurring translocations, mutations and epigenetic alterations, as well as describe traditional and novel methods for diagnosis and analysis of these patients.

  5. Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia.

    Science.gov (United States)

    Yamada, S; Hongo, T; Okada, S; Watanabe, C; Fujii, Y; Ohzeki, T

    2001-12-01

    To determine the clinical relevance of in vitro drug chemoresistance in childhood acute myeloid leukemia, we used an MTT assay to test leukemic cells from 132 newly diagnosed children. Patients were diagnosed according to the French-American-British (FAB) classification as follows: M0 (n = 12), M1 (n = 16), M2 (n = 53), M4 (n = 17), M5 (n = 19) and M7 (n = 15). The results revealed that, compared to leukemic cells from complete-responders (n = 107), those from non-responders who failed induction therapy (n = 17) were 1.4 to 5.0 times more resistant in vitro to cytarabine (P = 0.005), melphalan (P = 0.003), etoposide (P = 0.011), L-asparaginase (P = 0.017), aclarubicin (P = 0.026) and dexamethasone (P = 0.039). For seven other drugs tested, the median lethal dose of 70% and leukemic cell survival of non-responders were higher than those of complete-responders, but the difference was not statistically significant. We sought correlations between FAB subtypes and in vitro drug resistance. Leukemias of the FAB M4 and M5 subtype were more sensitive to L-asparaginase (P = 0.01, P = 0.0036) than those of the FAB M2 subtype. FAB M5 leukemia was more sensitive to etoposide than were the FAB M2, M4 and M7 subtypes (P = 0.001, P = 0.034, P = 0.023, respectively). By contrast, FAB M5 leukemia was significantly more resistant to prednisolone and dexamethasone than were the FAB M0, M1, M2, M4 and M7 subtypes. We sought correlations between in vitro drug resistance and long-term clinical outcome, but found no associations in this case. These results suggest that in vitro resistance to cytarabine, melphalan, etoposide, L-asparaginase, aclarubicin and dexamethasone might represent factors that can predict response to the early course of therapy. Selecting an appropriate anti-cancer drug according to the FAB classification together with drug sensitivity testing may contribute to improved prognoses in childhood acute myeloid leukemia.

  6. Characterization of the translocation breakpoint sequences of two DEK-CAN fusion genes present in t(6;9) acute myeloid leukemia and a SET-CAN fusion gene found in a case of acute undifferentiated leukemia

    NARCIS (Netherlands)

    von Lindern, M.; Breems, D.; van Baal, S.; Adriaansen, H.; Grosveld, G.

    1992-01-01

    The t(6;9) associated with a subtype of acute myeloid leukemia (AML) was shown to generate a fusion between the 3' part of the CAN gene on chromosome 9 and the 5' part of the DEK gene on chromosome 6. The same part of the CAN gene appeared to be involved in a case of acute undifferentiated leukemia

  7. Cyanobacteria from Terrestrial and Marine Sources Contain Apoptogens Able to Overcome Chemoresistance in Acute Myeloid Leukemia Cells

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    Liwei Liu

    2014-04-01

    Full Text Available In this study, we investigated forty cyanobacterial isolates from biofilms, gastropods, brackish water and symbiotic lichen habitats. Their aqueous and organic extracts were used to screen for apoptosis-inducing activity against acute myeloid leukemia cells. A total of 28 extracts showed cytotoxicity against rat acute myeloid leukemia (IPC-81 cells. The design of the screen made it possible to eliminate known toxins, such as microcystins and nodularin, or known metabolites with anti-leukemic activity, such as adenosine and its analogs. A cytotoxicity test on human embryonic kidney (HEK293T fibroblasts indicated that 21 of the 28 extracts containing anti-acute myeloid leukemia (AML activity showed selectivity in favor of leukemia cells. Extracts L26-O and L30-O were able to partly overcome the chemotherapy resistance induced by the oncogenic protein Bcl-2, whereas extract L1-O overcame protection from the deletion of the tumor suppressor protein p53. In conclusion, cyanobacteria are a prolific resource for anti-leukemia compounds that have potential for pharmaceutical applications. Based on the variety of cellular responses, we also conclude that the different anti-leukemic compounds in the cyanobacterial extracts target different elements of the death machinery of mammalian cells.

  8. Chronic myeloid leukemia may be associated with several bcr-abl transcripts including the acute lymphoid leukemia-type 7 kb transcript

    NARCIS (Netherlands)

    Selleri, L.; von Lindern, M.; Hermans, A.; Meijer, D.; Torelli, G.; Grosveld, G.

    1990-01-01

    In the majority of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) patients, the c-abl gene is fused to the bcr gene, resulting in the transcription of an 8.5 kb chimeric bcr-abl mRNA, which is translated into a p210bcr-abl fusion protein. In about 50% of the Ph-positive acute lymphoid

  9. Aberrant lymphoid antigen expression in acute myeloid leukemia in Saudi Arabia.

    Science.gov (United States)

    El-Sissy, Azza H; El-Mashari, May A; Bassuni, Wafaa Y; El-Swaayed, Aziza F

    2006-09-01

    Immunophenotyping improves both accuracy and reproducibility of acute leukemia classification and is considered particularly useful for identifying aberrant lineage association of acute leukemia, biphenotypic and bilineal acute leukemia, as well as monitoring minimal residual disease. Some immunophenotypes correlate with cytogenetic abnormalities and prognosis. Is to determine aberrant lymphoid antigen expression in Saudi acute myeloid leukemia (AML), correlate them with FAB subtypes, evaluate early surface markers CD7 and CD56, and to investigate the role of cytoplasmic CD79a (a B cell marker that is assigned a high score of 2.0 in the WHO classification). Thirty four newly diagnosed AML cases were included in this study, 47% showed aberrant lymphoid antigen expression. CD9 was the most frequently expressed lymphoid antigen (29.4%) followed by CD7 & CD19 (11.8%), CD4 (8.8%) and CD22 (2.9%). CD9 was expressed in 3/6 (50%) of M3 cases, CD7 was expressed in 11.8% and was mostly confined to FAB M1 and M2 and associated with immature antigens CD34, HLA-DR and TdT. CD56 was expressed in 7/34 (20.6%) cases, three of these cases (42.9%) belonged to the monocytic group. CD56 was also detected in 2 cases with 11q23 rearrangement. CD56 was expressed in 2/7 (28.6%) M2 cases, and was associated with t (8;21) (q22;q22) together with CD19. Co-expression of CD56 and CD7 was detected in 2.9% of the cases. CD79a was expressed in one case together with CD19, diagnosed as acute biphenotypic leukemia, and was associated with t(8;21) (q22;q22). Minimal residual disease in AML is very difficult to trace, detection of aberrant expression of lymphoid antigens will make it easier. The high score given to CD79a by EGIL is questionable based on cytogenetic classification.

  10. Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

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    Alba Maiques-Diaz

    2018-03-01

    Full Text Available Summary: Pharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes. : Maiques-Diaz et al. report that, while LSD1 inhibitors target both scaffolding and enzymatic functions of the protein, drug-induced myeloid leukemia cell differentiation is primarily due to the disruption and release from enhancers of GFI1/CoREST complexes, leading to the activation of subordinate myeloid transcription factor genes. Keywords: LSD1, GFI1, acute myeloid leukemia, MLL, acetylation, methylation

  11. Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

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    Nestor R. Ramos

    2015-04-01

    Full Text Available The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor burden to a level sufficient to meet the current criteria for “complete” remission. Nevertheless, most AML patients ultimately die from their disease, most commonly as clinically evident relapsed AML. Despite a variety of available salvage therapy options, prognosis in patients with relapsed or refractory AML is generally poor. In this review, we outline the commonly utilized salvage cytotoxic therapy interventions and then highlight novel investigational efforts currently in clinical trials using both pathway-targeted agents and immunotherapy based approaches. We conclude that there is no current standard of care for adult relapsed or refractory AML other than offering referral to an appropriate clinical trial.

  12. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Göllner, Stefanie; Oellerich, Thomas; Agrawal-Singh, Shuchi

    2017-01-01

    In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction...... of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells...... in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML...

  13. Acute Myeloid Leukemia in a Patient With X-linked Severe Combined Immunodeficiency.

    Science.gov (United States)

    Shigemura, Tomonari; Motobayashi, Mitsuo; Matsuda, Kazuyuki; Shimodaira, Takahiro; Kurata, Takashi; Kobayashi, Norimoto; Agematsu, Kazunaga; Nakazawa, Yozo

    2017-11-01

    Severe combined immunodeficiency (SCID) is a defect in the differentiation and function of T cells. An increased malignancy risk, mainly lymphatic malignancy, has been described in patients with SCID. We report a patient with X-linked SCID who developed acute myeloid leukemia, derived from the recipient with somatic NRAS mutation 4 months after cord blood transplantation (CBT). Loss of heterozygosity phenomenon of the recipient at 6q14 locus was observed at 2 months post-CBT and progressed to 6q deletion (6q-) chromosome abnormality. Somatic NRAS mutation was detected at 3 months post-CBT. Thus, 6q- and NRAS mutation were strongly associated with the leukemic transformation in our patient.

  14. Tetraspanin CD81 is an adverse prognostic marker in acute myeloid leukemia.

    Science.gov (United States)

    Boyer, Thomas; Guihard, Soizic; Roumier, Christophe; Peyrouze, Pauline; Gonzales, Fanny; Berthon, Céline; Quesnel, Bruno; Preudhomme, Claude; Behal, Hélène; Duhamel, Alain; Roche-Lestienne, Catherine; Cheok, Meyling

    2016-09-20

    CD81 is a cell surface protein which belongs to the tetraspanin family. While in multiple myeloma its expression on plasma cells is associated with worse prognosis, this has not yet been explored in acute myeloid leukemia (AML). We measured membrane expression of CD81 on AML cells at diagnosis, evaluated its association with AML characteristics and its influence on patient outcome after intensive chemotherapy in a cohort of 134 patients. CD81 was detected in 92/134 (69%) patients. Patients with AML expressing CD81 had elevated leukocyte count (P=0.02) and were more likely classified as intermediate or adverse-risk by cytogenetics (Pclassification and a potential therapeutic target for drug development in AML.

  15. SYK is a critical regulator of FLT3 in acute myeloid leukemia.

    Science.gov (United States)

    Puissant, Alexandre; Fenouille, Nina; Alexe, Gabriela; Pikman, Yana; Bassil, Christopher F; Mehta, Swapnil; Du, Jinyan; Kazi, Julhash U; Luciano, Frédéric; Rönnstrand, Lars; Kung, Andrew L; Aster, Jon C; Galinsky, Ilene; Stone, Richard M; DeAngelo, Daniel J; Hemann, Michael T; Stegmaier, Kimberly

    2014-02-10

    Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Radiation-induced chromosome aberrations in bone marrow cells leading to acute myeloid leukemia in mouse

    International Nuclear Information System (INIS)

    Nobuhiko Ban; Tomoko Kusama

    1996-01-01

    It is well known that radiation-induced acute myeloid leukemia (RI-AML) in mice is charaterized by deletion and/or rearrangement of chromosome 2. While chromosome 2 has been suspected to be a target of RI-AML, radiation-sensitive site of the chromosome might be implicated in the leukemogenesis. There were few cytogenetical studies, however, focusing on chromosomal rearrangements shortly after irradiation, and little was known about the frequency and pattern of chromosome 2 aberrations during the early period. In this study, metaphase samples were prepared from whole-body irradiated mice 24 hours after irradiation, most of the cells considered to be in the first mitotic stage. Distribution of chromosomal breakpoints on the metaphase samples were analyzed to study the relationship between chromosome aberrations and RI-AML. (author)

  17. Successful treatment of Pseudomembranous necrotizing Aspergillus tracheobronchitis in a patient with acute myeloid leukemia

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    Stanić Jelena

    2014-01-01

    Full Text Available Introduction. Pseudomembranous necrotizing Aspergillus tracheobronchitis is a rare form of pulmonary aspergillosis which occurs in immunocompromised patients. Case Outline. A female patient aged 71, suffering from acute myeloid leukemia, developed the symptoms of progressive shortness of breath and inspiratory stridor. The diagnosis in our case was made on the histological findings from tissues obtained by bronchoscopy. A chest CT scan suggested the state of the compromised trachea and left principal bronchus lumen. The long-term regimen with itraconazole in the dose of 400 mg/24 hours proved efficient in our patient. Conclusion. Progressive shortness of breath and inspiratory stridor in immunocompromised patients along with radiological and CT changes should be also considered as pulmonary aspergillosis in differential diagnosis. [Projekat Ministarstva nauke Republike Srbije, br. 175056

  18. Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia

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    Mingxue Fan

    2017-08-01

    Full Text Available Abstract Currently, conventional therapies for acute myeloid leukemia (AML have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.

  19. Genetics Home Reference: chronic myeloid leukemia

    Science.gov (United States)

    ... Home Health Conditions Chronic myeloid leukemia Chronic myeloid leukemia Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Chronic myeloid leukemia is a slow-growing cancer of the blood- ...

  20. Influence of Chemotherapy on the Lipid Peroxidation and Antioxidant Status in Patients with Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Zohreh Sanaat

    2012-07-01

    Full Text Available Chemotherapeutic agents used in patients with cancer cause to generate the enormous amounts of free radicals associated with cell injury. In this study we assess the effects of chemotherapy regimen on oxidant/antioxidant status in patients with acute myeloid leukemia (AML. 38 newly diagnosed patients with acute myeloid leukemia were recruited in this study. All patients received cytarabine and daunorubicin as chemotherapy regimen. Plasma levels of malondialdehyde (MDA, total antioxidant status (TAS, and the levels of erythrocyte activity of superoxide dismutase (SOD and glutathione peroxidase (GPx were determined before chemotherapy and 14 days after chemotherapy with cytarabine and daunorubicin. Plasma MDA concentrations increased significantly (from 2.68±0.89 nmol/L to 3.14±1.29 nmol/L during the 14days post-chemotherapy period (P=0.04. Plasma TAS concentrations changed with chemotherapy from 1.09±0.15 mmol/L to 1.02±0.14 mmol/L with P=0.005. Erythrocyte SOD and GPX activity decreased overtime from 1157.24±543.61 U/g Hb to 984.01±419.09 U/g Hb (P=0.04 and 46.96±13.70 U/g Hb to 41.40±6.44 U/g Hb (P=0.02 respectively. We report here that there is an increase in malondialdehyde levels and a decrease in the levels of antioxidant enzymes and total antioxidant status. This suggests that chemotherapy causes these changes as a result of enormous production of reactive oxygen species in the patients with AML. Antioxidant supplementation must be approached with caution because of the probability of reduction the therapeutic efficacy of these cytotoxic drugs.

  1. A segmentation method based on HMRF for the aided diagnosis of acute myeloid leukemia.

    Science.gov (United States)

    Su, Jie; Liu, Shuai; Song, Jinming

    2017-12-01

    The diagnosis of acute myeloid leukemia (AML) is purely dependent on counting the percentages of blasts (>20%) in the peripheral blood or bone marrow. Manual microscopic examination of peripheral blood or bone marrow aspirate smears is time consuming and less accurate. The first and very important step in blast recognition is the segmentation of the cells from the background for further cell feature extraction and cell classification. In this paper, we aimed to utilize computer technologies in image analysis and artificial intelligence to develop an automatic program for blast recognition and counting in the aspirate smears. We proposed a method to analyze the aspirate smear images, which first performs segmentation of the cells by k-means cluster, then builds cell image representing model by HMRF (Hidden-Markov Random Field), estimates model parameters through probability of EM (expectation maximization), carries out convergence iteration until optimal value, and finally achieves second stage refined segmentation. Furthermore, the segmentation results are compared with several other methods using six classes of cells respectively. The proposed method was applied to six groups of cells from 61 bone marrow aspirate images, and compared with other algorithms for its performance on the analysis of the whole images, the segmentation of nucleus, and the efficiency of calculation. It showed improved segmentation results in both the cropped images and the whole images, which provide the base for down-stream cell feature extraction and identification. Segmentation of the aspirate smear images using the proposed method helps the analyst in differentiating six groups of cells and in the determination of blasts counting, which will be of great significance for the diagnosis of acute myeloid leukemia. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Improved outcome of childhood acute myeloid leukemia in an Eastern European country: Lithuanian experience.

    Science.gov (United States)

    Kairiene, Igne; Pasauliene, Ramune; Lipunova, Nadezda; Vaitkeviciene, Goda; Rageliene, Lina; Rascon, Jelena

    2017-10-01

    The reported treatment outcomes of children treated for cancer in Eastern European countries are inferior to those in Northern/Western Europe. We hypothesized that recent survival rates could be comparable to the current standards and performed a population-based analysis of treatment outcome of childhood acute myeloid leukemia (AML) in Lithuania, a small Eastern European country. Children childhood cancer, with an overall survival (OS) rate of > 80% in high-income countries. The difference in survival rates between Northern/Western and Eastern European countries as well as between high- and middle-/low-income countries is as much as 20%. Recently, the 5-year event-free survival rate of acute myeloid leukemia (AML) has reached > 60% in high-income countries. The survival rates for myeloproliferative diseases were the lowest in Eastern European countries. • The reported inferior survival rates were calculated based on outcome data of patients treated until 2007. The recent survival rates in Eastern European countries are unknown. What is New: • Being a small Eastern European country, Lithuania has experienced good economic growth during the last decade. We hypothesized that economic growth and gain of experience could result in better survival rates of children treated for cancer in our country in recent years. • A population-based analysis of treatment outcome of childhood AML treated in Lithuania in the recent years was performed for the first time. The survival rates of childhood AML in Lithuania are comparable to those of other high-income countries. Current survival rates of children treated for cancer in Eastern European countries could be comparable to the best current standards contributing to better European survival rates of childhood cancer in general.

  3. Association of Therapy for Autoimmune Disease With Myelodysplastic Syndromes and Acute Myeloid Leukemia.

    Science.gov (United States)

    Ertz-Archambault, Natalie; Kosiorek, Heidi; Taylor, Gretchen E; Kelemen, Katalin; Dueck, Amylou; Castro, Janna; Marino, Robert; Gauthier, Susanne; Finn, Laura; Sproat, Lisa Z; Palmer, Jeanne; Mesa, Ruben A; Al-Kali, Aref; Foran, James; Tibes, Raoul

    2017-07-01

    Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon. To query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm. This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio. Odds ratio (OR) assessment for AID-directed therapies. Among the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti-tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.

  4. Prognostic Significance of the Lymphoblastic Leukemia-Derived Sequence 1 (LYL1 Gene Expression in Egyptian Patients with Acute Myeloid Leukemia

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    Nadia El Menshawy

    2014-06-01

    Full Text Available OBJECTIVE: Aberrant activation of transcription factor genes is the most frequent target of genetic alteration in lymphoid malignancies. The lymphoblastic leukemia-derived sequence 1 (LYL1 gene, which encodes a basic helix-loop helix, was first identified with human T-cell acute leukemia. Recent studies suggest its involvement in myeloid malignancies. We aimed to study the expression percent of oncogene LYL1 in primary and secondary high-risk myeloid leukemia and the impact on prognostic significance in those patients. METHODS: Using quantitative real-time polymerase chain reaction for detection of LYL1 oncogenes, our study was carried out on 39 myeloid leukemia patients including de novo cases, myelodysplastic syndrome (MDS with transformation, and chronic myelogenous leukemia (CML in accelerated and blast crisis, in addition to 10 healthy individuals as the reference control. RESULTS: LYL1 expression was increased at least 2 times compared to the controls. The highest expression of this transcription factor was observed in the MDS cases transformed to acute leukemia at 7.3±3.1, p=0.0011. LYL1 expression was found in 68.2%, 75%, and 77.8% of cases of acute myeloid leukemia, CML crisis, and MDS, respectively. Significant correlation of LYL1 overexpression with some subtypes of French-American-British classification was found. There was, for the first time, significant correlation between the blood count at diagnosis and LYL1 expression (p=0.023, 0.002, and 0.031 for white blood cells, hemoglobin, and platelets, respectively. The rate of complete remission was lower with very high levels of LYL1 expression and the risk of relapse increased with higher levels of LYL1 expression, suggesting an unfavorable prognosis for cases with enhanced expression. CONCLUSION: Overexpression of LYL1 is highly associated with acute myeloid leukemia and shows more expression in MDS with unfavorable prognosis in response to induction chemotherapy. These

  5. Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia

    International Nuclear Information System (INIS)

    Raponi, Mitch; Belly, Robert T; Karp, Judith E; Lancet, Jeffrey E; Atkins, David; Wang, Yixin

    2004-01-01

    Farnesyl protein transferase inhibitors (FTIs) were originally developed to inhibit oncogenic ras, however it is now clear that there are several other potential targets for this drug class. The FTI tipifarnib (ZARNESTRA™, R115777) has recently demonstrated clinical responses in adults with refractory and relapsed acute leukemias. This study was conducted to identify genetic markers and pathways that are regulated by tipifarnib in acute myeloid leukemia (AML). Tipifarnib-mediated gene expression changes in 3 AML cell lines and bone marrow samples from two patients with AML were analyzed on a cDNA microarray containing approximately 7000 human genes. Pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis tool. The expression analysis identified a common set of genes that were regulated by tipifarnib in three leukemic cell lines and in leukemic blast cells isolated from two patients who had been treated with tipifarnib. Association of modulated genes with biological functional groups identified several pathways affected by tipifarnib including cell signaling, cytoskeletal organization, immunity, and apoptosis. Gene expression changes were verified in a subset of genes using real time RT-PCR. Additionally, regulation of apoptotic genes was found to correlate with increased Annexin V staining in the THP-1 cell line but not in the HL-60 cell line. The genetic networks derived from these studies illuminate some of the biological pathways affected by FTI treatment while providing a proof of principle for identifying candidate genes that might be used as surrogate biomarkers of drug activity

  6. Relation of BAALC and ERG Gene Expression with Overall Survival in Acute Myeloid Leukemia Cases.

    Science.gov (United States)

    Rashed, Reham A; Kadry, Dalia Y; El Taweel, Maha; Abd El Wahab, Nahed; Abd El Hameed, Thoreya

    2015-01-01

    The objectives of this study were to evaluate the expression of brain and acute leukemia, cytoplasmic (BAALC) gene and erythroblast transformation-specific related gene (ERG) in de novo cases of acute myeloid leukemia (AML) and identify roles in disease progression and outcome. This study included 50 newly diagnosed AML patients, along with 10 apparently healthy normal controls. BAALC and ERG expression was detected in the bone marrow of both patients and controls using real-time RT-PCR. BAALC and ERG expression was detected in 52% of cases but not in any controls. There was a statistically significant correlation between BAALC and ERG gene expression and age (p- value=0.004 and 0.019, respectively). No statistical significance was noted for sex, lymphadenopathy, hepatomegaly, splenomegaly, other hematological findings, immunophenotyping and FAB sub-classification except for ERG gene and FAB (p-value=0.058). A statistical significant correlation was found between response to treatment with ERG expression (p-value=0.028) and age (p-value=0.014). A statistically significant variation in overall survival was evident with patient age, BM blast cells, FAB subgroups, BAALC and ERG expression (p-value= <0.001, 0.045, 0.041, <0.008 and 0.025 respectively). Our results suggest that BAALC and ERG genes are specific significant molecular markers in AML disease progression, response to treatment and survival.

  7. Intensive induction is effective in selected octogenarian acute myeloid leukemia patients: prognostic significance of karyotype and selected molecular markers used in the European LeukemiaNet classification.

    Science.gov (United States)

    Wetzler, Meir; Mrózek, Krzysztof; Kohlschmidt, Jessica; Dombret, Hervé; Döhner, Hartmut; Pilorge, Sylvain; Krug, Utz; Carroll, Andrew J; Larson, Richard A; Marcucci, Guido; Hiddemann, Wolfgang; Büchner, Thomas; Bloomfield, Clara D

    2014-02-01

    We investigated whether octogenarian patients with acute myeloid leukemia enrolled onto Cooperative Group clinical trials and treated with intensive induction therapy could be cured, and whether karyotype and selected molecular markers had any prognostic significance in these patients. Among 138 patients with cytogenetic information, normal karyotype was the most common (47.1%) followed by complex karyotype (14.5%) and sole +8 (9.4%). Among these patients, the relapse-free survival rate at 1 year was 37% and 13% at 3 years, and the respective overall survival rates were 24% and 8%. Whereas the 90 patients who survived beyond 30 days had the same relapse-free survival rates, their 1-year and 3-year overall survival rates were 36% and 11%, respectively. Of the 66 patients surviving beyond 30 days who could be classified into European LeukemiaNet genetic groups, those in the intermediate-I group had better overall survival than patients in the adverse group (P=0.01). Among patients with cytogenetically normal acute myeloid leukemia who were tested for the European LeukemiaNet-associated molecular alterations, FLT3-internal tandem duplication and NPM1 mutations, it was found that FLT3-internal tandem duplication (detected in 29% of patients) did not associate with overall survival (P=0.31), whereas NPM1 mutations (30%) were associated with a significantly longer overall survival (P=0.002). We conclude that intensive induction is effective and indicated in selected octogenarians with acute myeloid leukemia, that their overall survival varies among the European LeukemiaNet genetic groups and that NPM1 mutations may be of prognostic significance among octogenarian patients with cytogenetically normal acute myeloid leukemia.

  8. The relationship between clinical feature, complex immunophenotype, chromosome karyotype, and outcome of patients with acute myeloid leukemia in China.

    Science.gov (United States)

    Ding, Bingjie; Zhou, Lanlan; Jiang, Xuejie; Li, Xiaodong; Zhong, Qingxiu; Wang, Zhixiang; Yi, Zhengshan; Zheng, Zhongxin; Yin, Changxin; Cao, Rui; Liao, Libin; Meng, Fanyi

    2015-01-01

    Mixed phenotype acute leukemia (MPAL) is a complex entity expressing both lymphoid and myeloid immunophenotyping. In the present study, 47 MPAL, 60 lymphoid antigen-positive acute myeloid leukemia (Ly(+)AML), and 90 acute myeloid leukemia with common myeloid immunophenotype (Ly(-)AML) patients were investigated. We found that, in MPAL patients, there were high proportions of blast cells in bone marrow and incidence of hepatosplenomegaly, lymphadenopathy, and Philadelphia chromosome. The overall survival (OS) and relapse-free survival (RFS) in MPAL patients were significantly shorter than those in Ly(+)AML and Ly(-)AML. With regard to the patients with normal karyotype only, the OS and RFS of MPAL were significantly lower than those of the Ly(+)AML and Ly(-)AML; but there were no significant differences in OS and RFS among the patients with complex karyotype. The OS rates of 3 groups with complex karyotype were lower than those of patients with normal karyotype. In Cox multivariate analysis, complex karyotype was an independent pejorative factor for both OS and RFS. Therefore, MPAL is confirmed to be a poor-risk disease while Ly(+)AML does not impact prognosis. Complex karyotype is an unfavorable prognosis factor in AML patients with different immunophenotype. Mixed immunophenotype and complex karyotype increase the adverse risk when they coexist.

  9. Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia.

    Science.gov (United States)

    De Luca, Luciana; Trino, Stefania; Laurenzana, Ilaria; Tagliaferri, Daniela; Falco, Geppino; Grieco, Vitina; Bianchino, Gabriella; Nozza, Filomena; Campia, Valentina; D'Alessio, Francesca; La Rocca, Francesco; Caivano, Antonella; Villani, Oreste; Cilloni, Daniela; Musto, Pellegrino; Del Vecchio, Luigi

    2017-06-01

    Lin28A is a highly conserved RNA-binding protein that concurs to control the balance between stemness and differentiation in several tissue lineages. Here, we report the role of miR-128a/Lin28A axis in blocking cell differentiation in acute myeloid leukemia (AML), a genetically heterogeneous disease characterized by abnormally controlled proliferation of myeloid progenitor cells accompanied by partial or total inability to undergo terminal differentiation. First, we found Lin28A underexpressed in blast cells from AML patients and AML cell lines as compared with CD34+ normal precursors. In vitro transfection of Lin28A in NPM1-mutated OCI-AML3 cell line significantly triggered cell-cycle arrest and myeloid differentiation, with increased expression of macrophage associate genes (EGR2, ZFP36 and ANXA1). Furthermore, miR-128a, a negative regulator of Lin28A, was found overexpressed in AML cells compared with normal precursors, especially in acute promyelocytic leukemia (APL) and in 'AML with maturation' (according to 2016 WHO classification of myeloid neoplasms and acute leukemia). Its forced overexpression by lentiviral infection in OCI-AML3 downregulated Lin28A with ensuing repression of macrophage-oriented differentiation. Finally, knockdown of miR-128a in OCI-AML3 and in APL/AML leukemic cells (by transfection and lentiviral infection, respectively) induced myeloid cell differentiation and increased expression of Lin28A, EGR2, ZFP36 and ANXA1, reverting myeloid differentiation blockage. In conclusion, our findings revealed a new mechanism for AML differentiation blockage, suggesting new strategies for AML therapy based upon miR-128a inhibition.

  10. Demographic and Clinical Characteristics of Adult Acute Myeloid Leukemia--Tertiary Care Experience.

    Science.gov (United States)

    Sultan, Sadia; Zaheer, Hasan Abbas; Irfan, Syed Mohammed; Ashar, Sana

    2016-01-01

    Acute myeloid leukemia (AML) is an acquired clonal frequent malignant disorder of myeloid progenitor cells. Our aim was to study demographical and clinicopathological features of adult Pakistani AML patients at presentation. In this single centre study extending from January 2010 to December 2014, data were retrieved from the patient records with a predetermined performa and analyzed with SPSS version 22. Overall 125 patients were diagnosed at our institution with de novo AML during the study period. There were 76 males and 49 females (ratio 1.5:1), with an age range between 15 and 85 years and a mean age of 38.8±20.1 years. The major complaints were fever (72.8%), generalized weakness (60%), bleeding (37.6%) and dyspnea (12%). Physical examination revealed pallor in 56.8%, splenomegaly and hepatomegaly in 16% and 12.8%, respectively, and lymphodenopathy in 10.4%. The mean hemoglobin was 8.19±2.12g/dl with a mean MCV of 86.0±9.83 fl, a mean total leukocyte count of 43.1±68.5x109/l, an ANC of 3.09±6.66x109/l and a mean platelet count of 62.3±78.6x109/l. AML in Pakistani patients is seen in a relatively very young population with male preponderance, compared with the west. However, clinico-pathological features appear comparable to published data.

  11. DNA Methylation Events as Markers for Diagnosis and Management of Acute Myeloid Leukemia and Myelodysplastic Syndrome

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    Geórgia Muccillo Dexheimer

    2017-01-01

    Full Text Available During the onset and progression of hematological malignancies, many changes occur in cellular epigenome, such as hypo- or hypermethylation of CpG islands in promoter regions. DNA methylation is an epigenetic modification that regulates gene expression and is a key event for tumorigenesis. The continuous search for biomarkers that signal early disease, indicate prognosis, and act as therapeutic targets has led to studies investigating the role of DNA in cancer onset and progression. This review focuses on DNA methylation changes as potential biomarkers for diagnosis, prognosis, response to treatment, and early toxicity in acute myeloid leukemia and myelodysplastic syndrome. Here, we report that distinct changes in DNA methylation may alter gene function and drive malignant cellular transformation during several stages of leukemogenesis. Most of these modifications occur at an early stage of disease and may predict myeloid/lymphoid transformation or response to therapy, which justifies its use as a biomarker for disease onset and progression. Methylation patterns, or its dynamic change during treatment, may also be used as markers for patient stratification, disease prognosis, and response to treatment. Further investigations of methylation modifications as therapeutic biomarkers, which may correlate with therapeutic response and/or predict treatment toxicity, are still warranted.

  12. New classification of acute myeloid leukemia and precursor-related neoplasms: changes and unsolved issues.

    Science.gov (United States)

    Falini, Brunangelo; Tiacci, Enrico; Martelli, Maria Paola; Ascani, Stefano; Pileri, Stefano A

    2010-10-01

    The World Health Organization (WHO) classification of lympho-hematopoietic neoplasms is increasingly based on genetic criteria. Here, we focus on changes that, as compared to the 2001 edition, were introduced into the 2008 WHO classification of acute myeloid leukemia (AML) and related precursor neoplasms. The category of AML with recurrent genetic abnormalities was expanded to account for 60% of AML by adding three distinct entities, i.e., AML with t(6,9), inv(3), or t(1;22), and two provisional entities, i.e., AML with mutated NPM1 or CEBPA. These changes have greatly modified the approaches to diagnosis and prognostic stratification of AML patients. To emphasize the need of various parameters for diagnosis, including myelodysplasia (MD)-related cytogenetic abnormalities, history of myelodysplasia or myelodysplasia/myeloproliferative neoplasm, and multilineage dysplasia, the category of "AML with multilineage dysplasia" was re-named AML with MD-related changes. Finally, we describe the unique characteristics of myeloid proliferations associated with Down syndrome and blastic plasmacytoid dendritic cell neoplasm.

  13. The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia.

    Science.gov (United States)

    Fenouille, Nina; Bassil, Christopher F; Ben-Sahra, Issam; Benajiba, Lina; Alexe, Gabriela; Ramos, Azucena; Pikman, Yana; Conway, Amy S; Burgess, Michael R; Li, Qing; Luciano, Frédéric; Auberger, Patrick; Galinsky, Ilene; DeAngelo, Daniel J; Stone, Richard M; Zhang, Yi; Perkins, Archibald S; Shannon, Kevin; Hemann, Michael T; Puissant, Alexandre; Stegmaier, Kimberly

    2017-03-01

    Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.

  14. Formaldehyde Exposure and Mortality Risks From Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute Cohort Study of Workers in Formaldehyde Industries

    Science.gov (United States)

    Dell, Linda D.; Boffetta, Paolo; Gallagher, Alexa E.; Crawford, Lori; Lees, Peter SJ.; Mundt, Kenneth A.

    2015-01-01

    Objectives: To evaluate associations between cumulative and peak formaldehyde exposure and mortality from acute myeloid leukemia (AML) and other lymphohematopoietic malignancies. Methods: Cox proportional hazards analyses. Results: Acute myeloid leukemia was unrelated to cumulative exposure. Hodgkin lymphoma relative risk estimates in the highest exposure categories of cumulative and peak exposures were, respectively, 3.76 (Ptrend = 0.05) and 5.13 (Ptrend = 0.003). There were suggestive associations with peak exposure observed for chronic myeloid leukemia, albeit based on very small numbers. No other lymphohematopoietic malignancy was associated with either chronic or peak exposure. Conclusions: Insofar as there is no prior epidemiologic evidence supporting associations between formaldehyde and either Hodgkin leukemia or chronic myeloid leukemia, any causal interpretations of the observed risk patterns are at most tentative. Findings from this re-analysis do not support the hypothesis that formaldehyde is a cause of AML. PMID:26147546

  15. Impact of ABO incompatibility on patients' outcome after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia - a report from the Acute Leukemia Working Party of the EBMT.

    Science.gov (United States)

    Canaani, Jonathan; Savani, Bipin N; Labopin, Myriam; Huang, Xiao-Jun; Ciceri, Fabio; Arcese, William; Tischer, Johanna; Koc, Yener; Bruno, Benedetto; Gülbas, Zafer; Blaise, Didier; Maertens, Johan; Ehninger, Gerhard; Mohty, Mohamad; Nagler, Arnon

    2017-06-01

    A significant proportion of hematopoietic stem cell transplants are performed with ABO-mismatched donors. The impact of ABO mismatch on outcome following transplantation remains controversial and there are no published data regarding the impact of ABO mismatch in acute myeloid leukemia patients receiving haploidentical transplants. Using the European Blood and Marrow Transplant Acute Leukemia Working Group registry we identified 837 patients who underwent haploidentical transplantation. Comparative analysis was performed between patients who received ABO-matched versus ABO-mismatched haploidentical transplants for common clinical outcome variables. Our cohort consisted of 522 ABO-matched patients and 315 ABO-mismatched patients including 150 with minor, 127 with major, and 38 with bi-directional ABO mismatching. There were no significant differences between ABO matched and mismatched patients in terms of baseline disease and clinical characteristics. Major ABO mismatching was associated with inferior day 100 engraftment rate whereas multivariate analysis showed that bi-directional mismatching was associated with increased risk of grade II-IV acute graft- versus -host disease [hazard ratio (HR) 2.387; 95% confidence interval (CI): 1.22-4.66; P =0.01). Non-relapse mortality, relapse incidence, leukemia-free survival, overall survival, and chronic graft- versus -host disease rates were comparable between ABO-matched and -mismatched patients. Focused analysis on stem cell source showed that patients with minor mismatching transplanted with bone marrow grafts experienced increased grade II-IV acute graft- versus -host disease rates (HR 2.03; 95% CI: 1.00-4.10; P =0.04). Patients with major ABO mismatching and bone marrow grafts had decreased survival (HR=1.82; CI 95%: 1.048 - 3.18; P =0.033). In conclusion, ABO incompatibility has a marginal but significant clinical effect in acute myeloid leukemia patients undergoing haploidentical transplantation. Copyright© Ferrata

  16. Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia.

    Science.gov (United States)

    Min, Chengyin; Moore, Nathan; Shearstone, Jeffrey R; Quayle, Steven N; Huang, Pengyu; van Duzer, John H; Jarpe, Matthew B; Jones, Simon S; Yang, Min

    2017-01-01

    Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have potential beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, primary leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.

  17. Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Chengyin Min

    Full Text Available Acute myeloid leukemia (AML is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have potential beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, primary leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.

  18. Pharmacologic Targeting of Chromatin Modulators As Therapeutics of Acute Myeloid Leukemia

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    Rui Lu

    2017-10-01

    Full Text Available Acute myeloid leukemia (AML, a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently “hit” genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event. Increasing body of evidence demonstrates that chromatin modification aberrations underlying the formation of blood cancer can be reversed by pharmacological targeting of the responsible epigenetic modulators, thus providing new mechanism-based treatment strategies. Here, we summarize recent advances in development of small-molecule inhibitors specific to chromatin factors and their potential applications in the treatment of genetically defined AMLs. These compounds selectively inhibit various subclasses of “epigenetic writers” (such as histone methyltransferases MLL/KMT2A, G9A/KMT1C, EZH2/KMT6A, DOT1L/KMT4, and PRMT1, “epigenetic readers” (such as BRD4 and plant homeodomain finger proteins, and “epigenetic erasers” (such as histone demethylases LSD1/KDM1A and JMJD2C/KDM4C. We also discuss about the molecular mechanisms underpinning therapeutic effect of these epigenetic compounds in AML and favor their potential usage for combinational therapy and treatment of pre-leukemia diseases.

  19. HA-1 T TCR T Cell Immunotherapy for the Treating of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant

    Science.gov (United States)

    2018-03-26

    HLA-A*0201 HA-1 Positive Cells Present; Minimal Residual Disease; Recurrent Acute Biphenotypic Leukemia; Recurrent Acute Undifferentiated Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  20. Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem cell functionality: a promising novel therapeutic target.

    Science.gov (United States)

    Etxabe, A; Lara-Castillo, M C; Cornet-Masana, J M; Banús-Mulet, A; Nomdedeu, M; Torrente, M A; Pratcorona, M; Díaz-Beyá, M; Esteve, J; Risueño, R M

    2017-11-01

    Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous neoplasia with poor outcome, organized as a hierarchy initiated and maintained by a sub-population with differentiation and self-renewal capacities called leukemia stem cells (LSCs). Although currently used chemotherapy is capable of initially reducing the tumor burden producing a complete remission, most patients will ultimately relapse and will succumb to their disease. As such, new therapeutic strategies are needed. AML cells differentially expressed serotonin receptor type 1 (HTR1) compared with healthy blood cells and the most primitive hematopoietic fraction; in fact, HTR1B expression on AML patient samples correlated with clinical outcome. Inhibition of HTR1s activated the apoptosis program, induced differentiation and reduced the clonogenic capacity, while minimal effect was observed on healthy blood cells. In vivo regeneration capacity of primary AML samples was disrupted upon inhibition of HTR1. The self-renewal capacity remaining in AML cells upon in vivo treatment was severely reduced as demonstrated by serial transplantation. Thus, treatment with HTR1 antagonists showed antileukemia effect, especially anti-LSC activity while sparing healthy blood cells. Our results highlight the importance of HTR1 in leukemogenesis and LSC survival and identify this receptor family as a new target for therapy in AML with prognostic value.

  1. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia.

    Science.gov (United States)

    Eghtedar, Alireza; Verstovsek, Srdan; Estrov, Zeev; Burger, Jan; Cortes, Jorge; Bivins, Carol; Faderl, Stefan; Ferrajoli, Alessandra; Borthakur, Gautam; George, Solly; Scherle, Peggy A; Newton, Robert C; Kantarjian, Hagop M; Ravandi, Farhad

    2012-05-17

    We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of treatment, and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 years (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with postmyeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) showed a significant response; 2 achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant reductions in spleen size. Overall, ruxolitinib was very well tolerated with only 4 patients having grade 3 or higher toxicity. Ruxolitinib has modest antileukemic activity as a single agent, particularly in patients with post-MPN AML. The study was registered at www.clinicaltrials.gov as NCT00674479.

  2. Association of loss of heterozygosity with cytogenetic abnormalities in acute myeloid leukemia and myelodysplastic syndrome

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    R.F. Pinheiro

    2008-07-01

    Full Text Available Deletions on chromosomes 5 and 7 are frequently seen in myelodysplastic syndrome (MDS and acute myeloid leukemia (AML. It is assumed that these deletions indicate loss of tumor suppressor genes on these chromosomes and until these tumor suppressor genes are identified, the functional consequences of these deletions and the molecular basis of these myeloid disorders cannot be completely understood. We evaluated loss of heterozygosity (LOH in 44 patients (18 MDS and 26 AML, diagnosed according to WHO classification criteria at diagnosis, using a four-microsatellite marker panel: an intragenic marker on the 7th intron of gene IRF-1 of the 5q31.1 region and three markers located inside the 7q31.1 region and correlated the LOH with karyotype abnormalities. The microsatellites chosen corresponded to chromosome regions frequently deleted in MDS/AML. The samples with Q (peak area less than or equal to 0.50 were indicative of LOH. The percent of informative samples (i.e., heterozygous for the intragenic microsatellite in gene IRF-1 and in loci D7S486, D7S515 and D7S522 were 66.6, 73.7, 75.5, and 48.8%, respectively. Cytogenetic abnormalities by G-banding were found in 36% (16/44 of the patients (2 of 18 MDS and 14 of 26 AML patients. We found a significantly positive association of the occurrence of LOH with abnormal karyotype (P < 0.05; chi-square test and there were cases with LOH but the karyotype was normal (by G-banding. These data indicate that LOH in different microsatellite markers is possibly an event previous to chromosomal abnormalities in these myeloid neoplasias.

  3. The role of HOXB2 and HOXB3 in acute myeloid leukemia

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    Lindblad, Oscar [Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund (Sweden); Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund (Sweden); Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund (Sweden); Chougule, Rohit A.; Moharram, Sausan A. [Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund (Sweden); Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund (Sweden); Kabir, Nuzhat N. [Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal (Bangladesh); Sun, Jianmin [Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund (Sweden); Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund (Sweden); Kazi, Julhash U. [Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund (Sweden); Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund (Sweden); Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal (Bangladesh); Rönnstrand, Lars, E-mail: lars.ronnstrand@med.lu.se [Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund (Sweden); Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund (Sweden)

    2015-11-27

    Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML.

  4. Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells

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    Del Pozzo Giovanna

    2009-06-01

    Full Text Available Abstract Background: BPA (bisphenol A or 2,2-bis(4-hydroxy-phenolpropane is present in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA. Thus, it is necessary to investigate the cytotoxicity and apoptosis-inducing activity of this compound. Methods: Cell cycle, apoptosis and differentiation analyses; western blots. Results: BPA is able to induce cell cycle arrest and apoptosis in three different acute myeloid leukemias. Although some granulocytic differentiation concomitantly occurred in NB4 cells upon BPA treatment, the major action was the induction of apoptosis. BPA mediated apoptosis was caspase dependent and occurred by activation of extrinsic and intrinsic cell death pathways modulating both FAS and TRAIL and by inducing BAD phosphorylation in NB4 cells. Finally, also non genomic actions such as the early decrease of both ERK and AKT phosphorylation were induced by BPA thus indicating that a complex intersection of regulations occur for the apoptotic action of BPA. Conclusion: BPA is able to induce apoptosis in leukemia cells via caspase activation and involvement of both intrinsic and extrinsic pathways of apoptosis.

  5. Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups.

    Science.gov (United States)

    Creutzig, Ursula; Zimmermann, Martin; Reinhardt, Dirk; Rasche, Mareike; von Neuhoff, Christine; Alpermann, Tamara; Dworzak, Michael; Perglerová, Karolína; Zemanova, Zuzana; Tchinda, Joelle; Bradtke, Jutta; Thiede, Christian; Haferlach, Claudia

    2016-12-15

    To obtain better insight into the biology of acute myeloid leukemia (AML) in various age groups, this study focused on the genetic changes occurring during a lifetime. This study analyzed the relation between age and genetics from birth to 100 years in 5564 patients with de novo AML diagnosed from 1998 to 2012 (1192 patients from nationwide pediatric studies [AML Berlin-Frankfurt-Münster studies 98 and 2004] and 4372 adults registered with the Munich Leukemia Laboratory). The frequencies of cytogenetic subgroups were age-dependent. Favorable subtypes (t(8;21), inv(16)/t(16;16), and t(15;17)) decreased in general from the pediatric age group (2 to groups ( 70 years; P age-specific incidence with age. Interestingly, the frequency of 11q23 abnormalities decreased from infants to older patients. The proportion of clinically relevant molecular aberrations of CCAAT/enhancer binding protein α, nucleophosmin (NPM1), and NPM1/fms-related tyrosine kinase 3-internal tandem duplication increased with age. Altogether, with the exclusion of infants, a significant decrease in the proportion of favorable cytogenetic subtypes and an increase in unfavorable cytogenetics were observed with increasing age. These findings indicate different mechanisms for the pathogenesis of AML; these different mechanisms also suggest directions for etiological research and contribute to the more unfavorable prognosis with increasing age. Cancer 2016;122:3821-3830. © 2016 American Cancer Society. © 2016 American Cancer Society.

  6. Eltrombopag modulates reactive oxygen species and decreases acute myeloid leukemia cell survival.

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    Anna Kalota

    Full Text Available Previous studies have demonstrated that the small molecule thrombopoietin (TPO mimetic, eltrombopag (E, induces apoptosis in acute myeloid leukemia (AML cells. Here, we sought to define the mechanism of the anti-leukemic effect of eltrombopag. Our studies demonstrate that, at a concentration of 5 μM E in 2% serum, E induces apoptosis in leukemia cells by triggering PARP cleavage and activation of caspase cascades within 2-6 hours. The induction of apoptotic enzymes is critically dependent on drug concentration and the concentration of serum. This effect is not associated with an alteration in mitochondrial potential but is associated with a rapid decrease in a reactive oxygen species (ROS in particular hydrogen peroxide (H2O2. Interestingly, E also decreases mitochondrial maximal and spare respiratory capacities suggesting an induced mitochondrial dysfunction that may not be readily apparent under basal conditions but becomes manifest only under stress. Co-treatment of MOLM14 AML cells with E plus Tempol or H2O2 provides a partial rescue of cell toxicity. Ferric ammonioum citrate (FAC also antagonized the E induced toxicity, by inducing notable increase in ROS level. Overall, we propose that E dramatically decreases ROS levels leading to a disruption of AML intracellular metabolism and rapid cell death.

  7. Pediatric acute myeloid leukemia as classified using 2008 WHO criteria: a single-center experience.

    Science.gov (United States)

    Davis, Kara L; Marina, Neyssa; Arber, Daniel A; Ma, Lisa; Cherry, Athena; Dahl, Gary V; Heerema-McKenney, Amy

    2013-06-01

    The classification of acute myeloid leukemia (AML) has evolved to the most recent World Health Organization (WHO) schema, which integrates genetic, morphologic, and prognostic data into a single system. However, this system was devised using adult data and how this system applies to a pediatric cohort is unknown. Performing a retrospective chart review, we examined our single-center experience with AML in 115 children and classified their leukemia using the WHO 2008 schema. We examined patient samples for mutations of FLT3, NPM1, and CEBPA. Overall survival was calculated within categories. In our pediatric population, most cases of AML had recurrent genetic abnormalities of favorable prognosis. More than 10% of patients in our series were categorized as AML, with myelodysplasia-related changes, an entity not well-described in pediatric patients. In addition, a large proportion of patients were categorized with secondary, therapy-related AML. To our knowledge, this is the first application of the WHO 2008 classification to a pediatric cohort. In comparison to adult studies, AML in the pediatric population shows a distinct distribution within the WHO 2008 classification.

  8. Validation of risk stratification models in acute myeloid leukemia using sequencing-based molecular profiling.

    Science.gov (United States)

    Wang, M; Lindberg, J; Klevebring, D; Nilsson, C; Mer, A S; Rantalainen, M; Lehmann, S; Grönberg, H

    2017-10-01

    Risk stratification of acute myeloid leukemia (AML) patients needs improvement. Several AML risk classification models based on somatic mutations or gene-expression profiling have been proposed. However, systematic and independent validation of these models is required for future clinical implementation. We performed whole-transcriptome RNA-sequencing and panel-based deep DNA sequencing of 23 genes in 274 intensively treated AML patients (Clinseq-AML). We also utilized the The Cancer Genome Atlas (TCGA)-AML study (N=142) as a second validation cohort. We evaluated six previously proposed molecular-based models for AML risk stratification and two revised risk classification systems combining molecular- and clinical data. Risk groups stratified by five out of six models showed different overall survival in cytogenetic normal-AML patients in the Clinseq-AML cohort (P-value0.5). Risk classification systems integrating mutational or gene-expression data were found to add prognostic value to the current European Leukemia Net (ELN) risk classification. The prognostic value varied between models and across cohorts, highlighting the importance of independent validation to establish evidence of efficacy and general applicability. All but one model replicated in the Clinseq-AML cohort, indicating the potential for molecular-based AML risk models. Risk classification based on a combination of molecular and clinical data holds promise for improved AML patient stratification in the future.

  9. Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia.

    Science.gov (United States)

    Bhola, Patrick D; Mar, Brenton G; Lindsley, R Coleman; Ryan, Jeremy A; Hogdal, Leah J; Vo, Thanh Trang; DeAngelo, Daniel J; Galinsky, Ilene; Ebert, Benjamin L; Letai, Anthony

    2016-10-03

    Upfront resistance to chemotherapy and relapse following remission are critical problems in leukemia that are generally attributed to subpopulations of chemoresistant tumor cells. There are, however, limited means for prospectively identifying these subpopulations, which hinders an understanding of therapeutic resistance. BH3 profiling is a functional single-cell analysis using synthetic BCL-2 BH3 domain-like peptides that measures mitochondrial apoptotic sensitivity or "priming." Here, we observed that the extent of apoptotic priming is heterogeneous within multiple cancer cell lines and is not the result of experimental noise. Apoptotic priming was also heterogeneous in treatment-naive primary human acute myeloid leukemia (AML) myeloblasts, and this heterogeneity decreased in chemotherapy-treated AML patients. The priming of the most apoptosis-resistant tumor cells, rather than the median priming of the population, best predicted patient response to induction chemotherapy. For several patients, these poorly primed subpopulations of AML tumor cells were enriched for antiapoptotic proteins. Developing techniques to identify and understand these apoptosis-insensitive subpopulations of tumor cells may yield insights into clinical chemoresistance and potentially improve therapeutic outcomes in AML.

  10. [High expression of p15 antisense RNA is a frequent event in acute myeloid leukemia].

    Science.gov (United States)

    Liao, Yufeng; Le, Donghai; Zhu, Zhankun

    2016-04-01

    To detect the presence of p15 antisense RNA(p15AS) in acute myeloid leukemia(AML). p15AS and p15 mRNA in two leukemia cell lines was detected with strand-specific primer RT-qPCR. To explore the connection between p15AS and AML, 43 patients with newly diagnosed AML and 21 patients with benign diseases (Iron deficiency anemia) as controls were enrolled. The expression level of p15AS in bone marrow cells derived from the patients and the controls were determined by strand-specific primer RT-qPCR, and its relationship with clinical features was analyzed. The two AML lines displayed high p15AS and low p15 expression. Samples derived from the AML patients showed relatively increased expression of p15AS and down-regulated p15 expression in their bone cells. In contrast, the 21 controls showed high expression of p15 but relatively low expression of the p15AS. Compared with the normal controls, the expression levels of p15 protein were significantly lower among the AML patients (PFAB subtype, total white blood cell count, platelet count, proliferative degree of bone marrow cell and karyotype classification (P>0.05 for all comparisons). High expression of p15 antisense RNA was frequently found among AML patients, and may play an important role in epigenetic silencing of p15.

  11. Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia.

    Science.gov (United States)

    Hirsch, Pierre; Tang, Ruoping; Abermil, Nassera; Flandrin, Pascale; Moatti, Hannah; Favale, Fabrizia; Suner, Ludovic; Lorre, Florence; Marzac, Christophe; Fava, Fanny; Mamez, Anne-Claire; Lapusan, Simona; Isnard, Françoise; Mohty, Mohamad; Legrand, Ollivier; Douay, Luc; Bilhou-Nabera, Chrystele; Delhommeau, François

    2017-07-01

    The genetic landscape of adult acute myeloid leukemias (AML) has been recently unraveled. However, due to their genetic heterogeneity, only a handful of markers are currently used for the evaluation of minimal residual disease (MRD). Recent studies using multi-target strategies indicate that detection of residual mutations in less than 5% of cells in complete remission is associated with a better survival. Here, in a series of 69 AMLs with known clonal architecture, we design a clone-specific strategy based on fluorescent in situ hybridization and high-sensitivity next generation sequencing to detect chromosomal aberrations and mutations, respectively, in follow-up samples. The combination of these techniques allows tracking chromosomal and genomic lesions down to 0.5-0.4% of the cell population in remission samples. By testing all lesions in follow-up samples from 65 of 69 evaluable patients, we find that initiating events often persist and appear to be, on their own, inappropriate markers to predict short-term relapse. In contrast, the persistence of two or more lesions in more than 0.4% of the cells from remission samples is strongly associated with lower leukemia-free and overall survivals in univariate and multivariate analyses. Although larger prospective studies are needed to extend these results, our data show that a personalized, clone-specific, MRD follow up strategy is feasible in the vast majority of AML cases. Copyright© 2017 Ferrata Storti Foundation.

  12. Central nervous system leukemia in a patient with concurrent nasopharyngeal carcinoma and acute myeloid leukaemia: A case report.

    Science.gov (United States)

    Liu, Jun-Qing; Mai, Wen-Yuan; Wang, Si-Ben; Lou, Yin-Jun; Yan, Sen-Xiang; Jin, Jie; Xu, Wei-Lai

    2017-12-01

    Concurrent case of nasopharyngeal carcinoma (NPC) and acute myeloid leukemia (AML) has not been reported. Here, we report a case of NPC, who was concurrently suffered from AML one mother after the NPC diagnosis. The patient was a 45-year-old male who presented with a mass on his right side neck. The patient was diagnosed with Epstein-Barr virus negative type-2 non-keratinizing carcinoma with clivus involvement and unilateral metastasis to the cervical lymph node. He was treated with one cycle of cisplatin and 69.76 Gy of concurrent external-beam radiation. Three months after completion of chemo-radiotherapy, the patient was diagnosed as acute myeloid leukemia, which achieved complete remission after one course induction chemotherapy. Two months later, however, the patient was diagnosed as central nervous system leukemia. He ultimately died of relapsed leukemia. The overall survival of the patient was 10 months. The co-occurrence of NPC and AML is rare and prognosis is poor. Radiotherapy in NPC can disrupt the blood-brain barrier, which may contribute to the pathogenesis of central nervous system leukemia. Early alert and prevention of central nervous system leukemia following radiotherapy in NPC patient is recommended. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

  13. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia

    DEFF Research Database (Denmark)

    Baron, F; Labopin, M; Niederwieser, D

    2012-01-01

    This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of rela...... of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P...

  14. Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries

    DEFF Research Database (Denmark)

    Wennström, Lovisa; Edslev, Pernille Wendtland; Abrahamsson, Jonas

    2016-01-01

    BACKGROUND: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited. PROCEDURE: We investigated disease characteristics and outcome...... countries. RESULTS: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients...... for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic...

  15. The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells.

    Science.gov (United States)

    Singh, Raminder; Fröbel, Julia; Cadeddu, Ron-Patrick; Bruns, Ingmar; Schroeder, Thomas; Brünnert, Daniela; Wilk, Christian Matthias; Zerbini, Luiz Fernando; Haas, Rainer; Czibere, Akos

    2012-02-01

    Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Treatment of patients suffering from high-risk AML as defined by clinical parameters, cytogenetics, and/or molecular analyses is often unsuccessful. OSI-461 is a pro-apoptotic compound that has been proposed as a novel therapeutic option for patients suffering from solid tumors like prostate or colorectal carcinoma. But little is known about its anti-proliferative potential in AML. Hence, we treated bone marrow derived CD34(+) selected blast cells from 20 AML patients and the five AML cell lines KG-1a, THP-1, HL-60, U-937, and MV4-11 with the physiologically achievable concentration of 1 μM OSI-461 or equal amounts of DMSO as a control. Following incubation with OSI-461, we found a consistent induction of apoptosis and an accumulation of cells in the G2/M phase of the cell cycle. In addition, we demonstrate that the OSI-461 mediated anti-proliferative effects observed in AML are associated with the induction of the pro-apoptotic cytokine mda-7/IL-24 and activation of the growth arrest and DNA-damage inducible genes (GADD) 45α and 45γ. Furthermore, OSI-461 treated leukemia cells did not regain their proliferative potential for up to 8 days after cessation of treatment following the initial 48 h treatment period with 1 μM OSI-461. This indicates sufficient targeting of the leukemia-initiating cells in our in vitro experiments through OSI-461. The AML samples tested in this study included samples from patients who were resistant to conventional chemotherapy and/or had FLT3-ITD mutations demonstrating the high potential of OSI-461 in human AML.

  16. The gene signature in CCAAT-enhancer-binding protein alpha dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors

    Czech Academy of Sciences Publication Activity Database

    Liss, A.; Ooi, C.; Zjablovskaja, Polina; Benoukraf, T.; Radomska, H.S.; Ju, C.; Wu, M.C.; Balaštík, Martin; Delwel, R.; Brdička, Tomáš; Tan, P.; Tenen, D.G.; Alberich-Jorda, Meritxell

    2014-01-01

    Roč. 99, č. 4 (2014), s. 697-705 ISSN 0390-6078 R&D Projects: GA MŠk LK21307; GA MŠk(CZ) LK11213 Grant - others:NIH(US) CA66996; NIH(US) CA118316 Institutional support: RVO:68378050 Keywords : C/EBPa * histone deacetylase inhibitor * acute myeloid leukemia Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.814, year: 2014

  17. Systemic mastocytosis uncommon in KIT D816V mutation positive core-binding factor acute myeloid leukemia

    DEFF Research Database (Denmark)

    Kristensen, Thomas; Preiss, Birgitte; Broesby-Olsen, Sigurd

    2012-01-01

    Abstract The KIT D816V mutation is detected in the vast majority of adult cases of systemic mastocytosis (SM). The mutation is also frequently detected in core-binding factor acute myeloid leukemia (CBF-AML) defined by the presence of t(8;21)(q22;q22); RUNX1-RUNX1T1 or inv(16)(p13.1;q22)/t(16;16)...

  18. Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia

    OpenAIRE

    Qian, Zhijian; Fernald, Anthony A.; Godley, Lucy A.; Larson, Richard A.; Le Beau, Michelle M.

    2002-01-01

    One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34+ hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to ...

  19. Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia.

    Science.gov (United States)

    Oran, Betül; Jorgensen, Jeff L; Marin, David; Wang, Sa; Ahmed, Sairah; Alousi, Amin M; Andersson, Borje S; Bashir, Qaiser; Bassett, Roland; Lyons, Genevieve; Chen, Julianne; Rezvani, Katy; Popat, Uday; Kebriaei, Partow; Patel, Keyur; Rondon, Gabriela; Shpall, Elizabeth J; Champlin, Richard E

    2017-01-01

    Our aim was to improve outcome prediction after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia by combining cytogenetic and molecular data at diagnosis with minimal residual disease assessment by multicolor flow-cytometry at transplantation. Patients with acute myeloid leukemia in first complete remission in whom minimal residual disease was assessed at transplantation were included and categorized according to the European LeukemiaNet classification. The primary outcome was 1-year relapse incidence after transplantation. Of 152 patients eligible, 48 had minimal residual disease at the time of their transplant. Minimal residual disease-positive patients were older, required more therapy to achieve first remission, were more likely to have incomplete recovery of blood counts and had more adverse risk features by cytogenetics. Relapse incidence at 1 year was higher in patients with minimal residual disease (32.6% versus 14.4%, P=0.002). Leukemia-free survival (43.6% versus 64%, P=0.007) and overall survival (48.8% versus 66.9%, P=0.008) rates were also inferior in patients with minimal residual disease. In multivariable analysis, minimal residual disease status at transplantation independently predicted 1-year relapse incidence, identifying a subgroup of intermediate-risk patients, according to the European LeukemiaNet classification, with a particularly poor outcome. Assessment of minimal residual disease at transplantation in combination with cytogenetic and molecular findings provides powerful independent prognostic information in acute myeloid leukemia, lending support to the incorporation of minimal residual disease detection to refine risk stratification and develop a more individualized approach during hematopoietic stem cell transplantation. Copyright© Ferrata Storti Foundation.

  20. Clinical efficacy and safety of imatinib in the management of Ph+ chronic myeloid or acute lymphoblastic leukemia in Chinese patients

    Science.gov (United States)

    Zhu, Yu; Qian, Si-Xuan

    2014-01-01

    Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukemia (CML) and functions by targeting BCR-ABL tyrosine kinases. Imatinib has substantially changed the clinical management and improved the prognosis of CML and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL). Here, we review the pharmacology, mode of action, and pharmacokinetics of imatinib; Chinese efficacy studies in CML and Ph+ ALL; safety and tolerability; patient-focused perspectives, such as quality of life, patient satisfaction, acceptability, and adherence; and uptake of imatinib. PMID:24623982

  1. Mutations in TET2 and DNMT3A genes are associated with changes in global and gene-specific methylation in acute myeloid leukemia.

    Science.gov (United States)

    Ponciano-Gómez, Alberto; Martínez-Tovar, Adolfo; Vela-Ojeda, Jorge; Olarte-Carrillo, Irma; Centeno-Cruz, Federico; Garrido, Efraín

    2017-10-01

    Acute myeloid leukemia is characterized by its high biological and clinical heterogeneity, which represents an important barrier for a precise disease classification and accurate therapy. While epigenetic aberrations play a pivotal role in acute myeloid leukemia pathophysiology, molecular signatures such as change in the DNA methylation patterns and genetic mutations in enzymes needed to the methylation process can also be helpful for classifying acute myeloid leukemia. Our study aims to unveil the relevance of DNMT3A and TET2 genes in global and specific methylation patterns in acute myeloid leukemia. Peripheral blood samples from 110 untreated patients with acute myeloid leukemia and 15 healthy control individuals were collected. Global 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA from peripheral blood leukocytes were measured by using the MethylFlashTM Quantification kits. DNMT3A and TET2 expression levels were evaluated by real-time quantitative polymerase chain reaction. The R882A hotspot of DNMT3A and exons 6-10 of TET2 were amplified by polymerase chain reaction and sequenced using the Sanger method. Methylation patterns of 16 gene promoters were evaluated by pyrosequencing after treating DNA with sodium bisulfite, and their transcriptional products were measured by real-time quantitative polymerase chain reaction.Here, we demonstrate altered levels of 5-methylcytosine and 5-hydroxymethylcytosine and highly variable transcript levels of DNMT3A and TET2 in peripheral blood leukocytes from acute myeloid leukemia patients. We found a mutation prevalence of 2.7% for DNMT3A and 11.8% for TET2 in the Mexican population with this disease. The average overall survival of acute myeloid leukemia patients with DNMT3A mutations was only 4 months. In addition, we showed that mutations in DNMT3A and TET2 may cause irregular DNA methylation patterns and transcriptional expression levels in 16 genes known to be involved in acute myeloid leukemia pathogenesis

  2. Patients with Acute Myeloid Leukemia Admitted to Intensive Care Units: Outcome Analysis and Risk Prediction.

    Science.gov (United States)

    Pohlen, Michele; Thoennissen, Nils H; Braess, Jan; Thudium, Johannes; Schmid, Christoph; Kochanek, Matthias; Kreuzer, Karl-Anton; Lebiedz, Pia; Görlich, Dennis; Gerth, Hans U; Rohde, Christian; Kessler, Torsten; Müller-Tidow, Carsten; Stelljes, Matthias; Hullermann, Carsten; Büchner, Thomas; Schlimok, Günter; Hallek, Michael; Waltenberger, Johannes; Hiddemann, Wolfgang; Berdel, Wolfgang E; Heilmeier, Bernhard; Krug, Utz

    2016-01-01

    This retrospective, multicenter study aimed to reveal risk predictors for mortality in the intensive care unit (ICU) as well as survival after ICU discharge in patients with acute myeloid leukemia (AML) requiring treatment in the ICU. Multivariate analysis of data for 187 adults with AML treated in the ICU in one institution revealed the following as independent prognostic factors for death in the ICU: arterial oxygen partial pressure below 72 mmHg, active AML and systemic inflammatory response syndrome upon ICU admission, and need for hemodialysis and mechanical ventilation in the ICU. Based on these variables, we developed an ICU mortality score and validated the score in an independent cohort of 264 patients treated in the ICU in three additional tertiary hospitals. Compared with the Simplified Acute Physiology Score (SAPS) II, the Logistic Organ Dysfunction (LOD) score, and the Sequential Organ Failure Assessment (SOFA) score, our score yielded a better prediction of ICU mortality in the receiver operator characteristics (ROC) analysis (AUC = 0.913 vs. AUC = 0.710 [SAPS II], AUC = 0.708 [LOD], and 0.770 [SOFA] in the training cohort; AUC = 0.841 for the developed score vs. AUC = 0.730 [SAPSII], AUC = 0.773 [LOD], and 0.783 [SOFA] in the validation cohort). Factors predicting decreased survival after ICU discharge were as follows: relapse or refractory disease, previous allogeneic stem cell transplantation, time between hospital admission and ICU admission, time spent in ICU, impaired diuresis, Glasgow Coma Scale intensive care.

  3. Targeted therapy for a subset of acute myeloid leukemias that lack expression of aldehyde dehydrogenase 1A1.

    Science.gov (United States)

    Gasparetto, Maura; Pei, Shanshan; Minhajuddin, Mohammad; Khan, Nabilah; Pollyea, Daniel A; Myers, Jason R; Ashton, John M; Becker, Michael W; Vasiliou, Vasilis; Humphries, Keith R; Jordan, Craig T; Smith, Clayton A

    2017-06-01

    Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is high in hematopoietic stem cells and functions in part to protect stem cells from reactive aldehydes and other toxic compounds. In contrast, we found that approximately 25% of all acute myeloid leukemias expressed low or undetectable levels of ALDH1A1 and that this ALDH1A1 - subset of leukemias correlates with good prognosis cytogenetics. ALDH1A1 - cell lines as well as primary leukemia cells were found to be sensitive to treatment with compounds that directly and indirectly generate toxic ALDH substrates including 4-hydroxynonenal and the clinically relevant compounds arsenic trioxide and 4-hydroperoxycyclophosphamide. In contrast, normal hematopoietic stem cells were relatively resistant to these compounds. Using a murine xenotransplant model to emulate a clinical treatment strategy, established ALDH1A1 - leukemias were also sensitive to in vivo treatment with cyclophosphamide combined with arsenic trioxide. These results demonstrate that targeting ALDH1A1 - leukemic cells with toxic ALDH1A1 substrates such as arsenic and cyclophosphamide may be a novel targeted therapeutic strategy for this subset of acute myeloid leukemias. Copyright© Ferrata Storti Foundation.

  4. Early Development of Acute Myeloid Leukemia Following Treatment of Osteosarcoma: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Yu-Mei Shen

    2009-10-01

    Full Text Available We report a case of treatment-related acute myeloid leukemia (t-AML in a 16-year-old male following treatment for osteosarcoma (OS. He had been treated with a protocol comprising neoadjuvant chemotherapy, definitive surgery with wide excision and adjuvant chemotherapy for OS. Four months after completion of the treatment, a routine hemogram showed hyperleukocytosis with 90% blasts. Bone marrow aspirate and a chromosomal analysis disclosed acute myeloid leukemia (AML, M5b with 46, XY, t(11;19(q23;p13.3. The t-AML was characterized by early development (just 4 months after completion of chemotherapy for OS and generalized leukemia cutis. The patient received an alkylating agent (ifosfamide and DNA topoisomerase II-targeted drugs (etoposide and doxorubicin. In terms of latency, cytogenetics, and presentation, DNA topoisomerase II-targeted drug-related leukemia seemed likely for this patient. Clinically, his leukemia cutis had developed during a nadir in white blood cell count after the first induction of chemotherapy for AML. The rapid progression and its refractoriness to chemotherapy were poor prognostic signs.

  5. Clathrin assembly lymphoid myeloid leukemia-AF10-positive acute leukemias: a report of 2 cases with a review of the literature.

    Science.gov (United States)

    Huh, Ji Young; Chung, Soie; Oh, Doyeun; Kang, Myung Seo; Eom, Hyeon Seok; Cho, Eun Hae; Han, Mi Hwa; Kong, Sun Young

    2010-04-01

    The translocation t(10;11)(p13;q14q21) has been found to be recurrent in acute lymphoblastic and myeloid leukemias, and results in the fusion of the clathrin assembly lymphoid myeloid leukemia (CALM) gene with the AF10 gene; these genes are present on chromosomes 11 and 10, respectively. Because the CALM-AF10 rearrangement is a rare chromosomal abnormality, it is not included in routine molecular tests for acute leukemia. Here, we describe the cases of 2 patients with the CALM-AF10 fusion gene. The first patient (case 1) was diagnosed with T-cell ALL, and the second patient (case 2) was diagnosed with AML. Both patient samples showed expression of the homeobox A gene cluster and the histone methyltransferase hDOT1L, which suggests that they mediate leukemic transformation in CALM-AF10-positive and mixed-lineage leukemia-AF10-positive leukemias. Both patients achieved complete remission after induction chemotherapy. The first patient (case 1) relapsed after double-unit cord blood transplantation; there was no evidence of relapse in the second patient (case 2) after allogenic peripheral blood stem cell transplantation. Since CALM-AF10- positive leukemias have been shown to have poor prognosis with conventional therapy, molecular tests for CALM-AF10 rearrangement would be necessary to detect minimal residual disease during follow-up.

  6. Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation

    Science.gov (United States)

    2018-02-22

    Newly Diagnosed Acute Myeloid Leukemia (AML); Untreated AML; AML Arising From Myelodysplastic Syndrome (MDS); AML Arising From Antecedent Hematologic Disorder (AHD); AML Arising After Exposure to Genotoxic Injury

  7. Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine 153 Malignant Pleural Effusion in Acute Myeloid Leukemia with Hepatitis B Virus Infection

    Directory of Open Access Journals (Sweden)

    C Suharti

    2016-05-01

    Full Text Available Pleural effusions can be the first presentation of a hematologic malignancy. The most common disorders with pleural effusion are Hodgkin and non-Hodgkin lymphoma with a frequency of 20 to 30%, especially if mediastinal involvement. Acute and chronic leukemia are rarely accompanied by pleural involvement. We describe a 46-year-old female with history of progressive dyspnoea. Physical examination was revealed massive left pleural effusion. Complete blood count revealed anemia, trombositopenia and normal leucocyte count. Viral serology test shown positive of HBsAg and total antiHBc. Chest X-ray revealed left pleural effusion. Pleural fluid cytology was myeloblast consistent with acute myeloid leukemia (AML. Bone marrow aspiration smear, bone marrow biopsy smear, and flow cytometry analysis were consistent with acute myeloid leukemia without maturation (AML M0-FAB classification. Key words: Acute myeloid leukemia, pleural effusion, infection.

  8. HES1 is an independent prognostic factor for acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Tian C

    2015-04-01

    Full Text Available Chen Tian, Yingjun Tang, Tengteng Wang, Yong Yu, Xiaofang Wang, Yafei Wang, Yizhuo ZhangKey laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of ChinaAbstract: HES1 is the target of Notch signaling which is reported to affect cell differentiation and maintain the cells in G0 phase in various tissues including the hematopoietic tissue. HES1 expression appears to be an independent prognostic factor for survival in a heterogeneous group of acute myeloid leukemia (AML patients. To better assess its significance, we analyzed HES1 expression in a group of non-core binding factor AML patients and correlated its expression with the overall survival and relapse-free survival of AML patients. First, we detected the messenger RNA expression of HES1 in 40 patients with AML by real-time polymerase chain reaction. The top 50% of AML cases with the high HES1 expression were compared with the rest of the AML cohort. Overall survival was calculated from the date of diagnosis until the date of death from any cause or until the date of final follow-up. Relapse-free survival was determined for responders from the time of diagnosis until relapse or death from any cause. We showed that the lower-expression group had a shorter overall survival time and shorter relapse-free survival time compared with those of the high-expression group (37.6±1.6 versus 54.0±1.3 months, 28.6±1.8 months versus 44.8±2.1 months, respectively, P<0.05, and Cox regression showed that HES1 was an independent prognostic factor. In all, we conclude that expression of HES1 is a useful prognostic factor for patients with non-core binding factor AML.Keywords: acute myeloid leukemia, HES1, prognostic factor

  9. Upregulation of microRNA-100 predicts poor prognosis in patients with pediatric acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Kuai W

    2012-09-01

    Full Text Available Jin Bai,1 Aiping Guo,2 Ze Hong,3 Wenxia Kuai31Department of Pediatrics, Huai'an Hospital to Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an, China; 2Department of Pediatrics, Chuzhou Hospital, Huai'an, China; 3Department of Pediatrics, Huai'an First People's Hospital, Huai'an, ChinaObjective: MicroRNA-100 (miR-100, a small noncoding RNA molecule, acts as a tumor suppressor or an oncogene in different cancers. The aberrant expression of this microRNA has been demonstrated as a frequent event in adult patients with acute myeloid leukemia (AML, but little is known for pediatric AML. The aim of this study was to investigate the expression and clinical significance of miR-100 in pediatric AML.Methods: The expression levels of miR-100 in bone marrow mononuclear cells were detected by real-time quantitative polymerase chain reaction in a cohort of 106 patients with de novo pediatric AML. The prognostic values of miR-100 in pediatric AML were also analyzed.Results: Compared with normal controls, upregulation of miR-100 in the bone marrow of pediatric AML patients with statistically significant differences (P < 0.001 was found. The expression levels of miR-100 were found to be significantly higher in pediatric AML patients with extramedullary disease, with the French–American–British classification subtype M7, and with unfavorable day 7 response to induction chemotherapy (P = 0.008, 0.001 and 0.01, respectively. Moreover, both univariate and multivariate analyses revealed that miR-100 upregulation was associated with poorer relapse-free and overall survival in pediatric AML patients.Conclusion: This is the first report demonstrating the upregulation of miR-100 in pediatric AML, and its association with poor relapse-free and overall survival. These results suggest that miR-100 upregulation may be used as an unfavorable prognostic marker in pediatric AML.Keywords: pediatric acute myeloid leukemia, microRNA-100, real

  10. Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Briot T

    2017-11-01

    Full Text Available Thomas Briot,1,2 Emilie Roger,1 Nolwenn Lautram,1 Alexis Verger,1 Anne Clavreul,3,4 Frederic Lagarce1,2 1Micro & Nanomédecines Translationelles – MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, MINT IBS-CHU, 2Pharmacy Department, University Hospital of Angers, 3Neurosurgery Department, University Hospital of Angers, 4CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France Abstract: Decitabine is a hydrophilic drug that acts by hypomethylating DNA. Decitabine is used in Europe for the treatment of acute myeloid leukemia (AML in patients aged ≥65 years. However, it can only be administered intravenously due to very low oral bioavailability and a large distribution volume. Oral administration would allow outpatient treatment, improving quality of life and reducing treatment costs. The present study proposes to develop lipid nanocapsules (LNCs, originally designed for lipophilic drugs, to encapsulate decitabine. Two different formulations of LNCs were designed: LNCs based on a high proportion of Transcutol® HP (THP-LNCs and LNCs associated with a mixture of Transcutol® HP and Tween® 80 (THP-T80-LNCs. The second formulation had a diameter of 26.5±0.5 nm, high encapsulation efficiency (>85%, and a drug payload of 472±64 µg/mL. Decitabine-loaded THP-T80-LNC cytotoxicity was evaluated on two AML cell lines depending on their decitabine resistance: HEL (not resistant and HL-60 (resistant. The permeability of decitabine-loaded THP-T80-LNCs was also evaluated on Caco-2 cell monolayers. Decitabine cytotoxicity against HEL and HL-60 was higher when decitabine was loaded in THP-T80-LNCs than when free. Apparent permeability on Caco-2 cell monolayers was also increased, suggesting a potentially useful formulation to increase the oral bioavailability of decitabine. Keywords: lipid nanocapsules, acute myeloid leukemia, decitabine, nanomedicine, nanoparticles, oral administration, Caco2 cells

  11. Molecular Study of Parvovirus B19 Infection in Children with Acute Myeloid Leukemia

    Science.gov (United States)

    Tharwat Abou El-Khier, Noha; Darwish, Ahmad; El Sayed Zaki, Maysaa

    2018-02-26

    Background: Parvovirus B19 is a common viral infection in children. Nearby evidences are present about its association with acute leukemia, especially acute lymphoblast leukemia. Nevertheless, scanty reports have discussed any role in acute myeloid leukemia (AML). Purpose: To evaluate the frequency of virological markers of B19 infection including its DNA along with specific immunoglobulins G (IgG) and M (IgM) among children with newly diagnosed AML. Besides, describing the clinical importance of Parvovirus B19 infection in those patients. Patients and methods: A case-control retrospective study was conducted on 48 children recently diagnosed with AML before and during chemotherapy induction and 60 healthy control. Specific serum IgM and IgG levels were determined by enzyme linked immunosorbant assay (ELISA) and DNA detection by polymerase chain reaction (PCR). Results: Parvovirus DNA was detected in 20 patients with AML. IgM was found in sera of four patients and one case had positive DNA and IgG (5%). Patients with recent parvovirus B19 infection had a significantly reduced hemoglobin levels, RBCs counts, platelet counts, neutrophil counts and absolute lymphocytosis (p=0.01, p=0.0001, p=0.01, p=0.02, p=0.0003, respectively). There were no clinical findings with statistically significant association to recent infection. Half of the patients with AML had positive PCR and/or IgM for parvovirus B19. Among children with AML under chemotherapy, there were reduced hemoglobin levels (P=0.03), reduced platelet counts (P=0.0001) and absolute neutropenia (mean±SD, 1.200 ±1.00) in those with parvovirus B19 infection. More than half of patients with parvovirus B19 (72.2%) had positive PCR and/or IgM and 36.4% of them had positive IgG. Conclusion: This study highlights that parvovirus B19 is common in children with AML either at diagnosis or under chemotherapy. There are no clinical manifestations that can be used as markers for its presence, but hematological laboratory

  12. An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells.

    Science.gov (United States)

    Zaidi, Sayyed K; Perez, Andrew W; White, Elizabeth S; Lian, Jane B; Stein, Janet L; Stein, Gary S

    2017-06-20

    Acute myeloid leukemia (AML) is characterized by an aggressive clinical course and frequent cytogenetic abnormalities that include specific chromosomal translocations. The 8;21 chromosomal rearrangement disrupts the key hematopoietic RUNX1 transcription factor, and contributes to leukemia through recruitment of co-repressor complexes to RUNX1 target genes, altered subnuclear localization, and deregulation of the myeloid gene regulatory program. However, a role of non-coding microRNAs (miRs) in t(8;21)-mediated leukemogenesis is minimally understood. We present evidence of an interplay between the tumor suppressor miR-29b-1 and the AML1-ETO (also designated RUNX1-RUNX1T1) oncogene that is encoded by the t(8;21). We find that AML1-ETO and corepressor NCoR co-occupy the miR-29a/b-1 locus and downregulate its expression in leukemia cells. Conversely, re-introduction of miR-29b-1 in leukemia cells expressing AML1-ETO causes significant downregulation at the protein level through direct targeting of the 3' untranslated region of the chimeric transcript. Restoration of miR-29b-1 expression in leukemia cells results in decreased cell growth and increased apoptosis. The AML1-ETO-dependent differentiation block and transcriptional program are partially reversed by miR-29b-1. Our findings establish a novel regulatory circuit between the tumor-suppressive miR-29b-1 and the oncogenic AML1-ETO that controls the leukemic phenotype in t(8;21)-carrying acute myeloid leukemia.

  13. Transfer of multidrug resistance among acute myeloid leukemia cells via extracellular vesicles and their microRNA cargo.

    Science.gov (United States)

    Bouvy, Céline; Wannez, Adeline; Laloy, Julie; Chatelain, Christian; Dogné, Jean-Michel

    2017-11-01

    The treatment of acute leukemia is still challenging due in part to the development of resistance and relapse. This chemotherapeutics resistance is established by clonal selection of resistant variants of the cancer cells. Recently, a horizontal transfer of chemo-resistance among cancer cells via extracellular vesicles (EVs) has been suggested. The aim of this research was to investigate the role of EVs in chemo-resistance in acute myeloid leukemia. For this purpose, the sensitive strain of the promyelocytic leukemia HL60 cell line was studied along with its multi-resistant strain, HL60/AR that overexpresses the multidrug resistance protein 1 (MRP-1). A chemo-resistance transfer between the two strains was established by treating HL60 cells with EVs generated by HL60/AR. This study reveals that EVs from HL60/AR can interact with HL60 cells and transfer at least partially, their chemo-resistance. EVs-treated cells begin to express MRP-1 probably due to a direct transfer of MRP-1 and nucleic acids transported by EVs. In this context, two microRNAs were highlighted for their high differential expression in EVs related to sensitive or chemo-resistant cells: miR-19b and miR-20a. Because circulating microRNAs are found in all biological fluids, these results bring out their potential clinical use as chemo-resistance biomarkers in acute myeloid leukemia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Enasidenib in mutantIDH2relapsed or refractory acute myeloid leukemia.

    Science.gov (United States)

    Stein, Eytan M; DiNardo, Courtney D; Pollyea, Daniel A; Fathi, Amir T; Roboz, Gail J; Altman, Jessica K; Stone, Richard M; DeAngelo, Daniel J; Levine, Ross L; Flinn, Ian W; Kantarjian, Hagop M; Collins, Robert; Patel, Manish R; Frankel, Arthur E; Stein, Anthony; Sekeres, Mikkael A; Swords, Ronan T; Medeiros, Bruno C; Willekens, Christophe; Vyas, Paresh; Tosolini, Alessandra; Xu, Qiang; Knight, Robert D; Yen, Katharine E; Agresta, Sam; de Botton, Stephane; Tallman, Martin S

    2017-08-10

    Recurrent mutations in isocitrate dehydrogenase 2 ( IDH2 ) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant- IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498. © 2017 by The American Society

  15. T-cell/myeloid mixed-phenotype acute leukemia with monocytic differentiation and isolated 17p deletion

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    Germison Silva Lopes

    2014-07-01

    Full Text Available Mixed phenotype acute leukemia is a rare subtype of leukemia that probably arises from a hematopoietic pluripotent stem cell. The co-expression of two of myeloid, B- or T-lymphoid antigens is the hallmark of this disease. Herein, the case of a 28-year-old female patient is reported who presented with hemoglobin of 5.8 g/dL, white blood cell count of 138 × 109/L and platelet count of 12 × 109/L. The differential count of peripheral blood revealed 96% of blasts. Moreover, the patient presented with lymphadenopathy, splenomegaly and bone marrow infiltration by monocytoid blasts characterized as 7% positivity by Sudan Black cytochemical staining. Immunophenotyping revealed the involvement of blasts of both T- and monocytic lineages. The cytogenetic analysis showed an isolated 17p deletion. Thus, the diagnosis of T-cell/myeloid mixed phenotype acute leukemia was made with two particular rare features, that is, the monocytic differentiation and the 17p deletion as unique cytogenetic abnormalities. The possibility of concomitant expressions of T-cell and monocytic differentiation antigens in the same blast population is hard to explain using the classical model of hematopoiesis. However, recent studies have suggested that myeloid potential persists even when the lineage branches segregate toward B- and T-cells. The role of an isolated 17p deletion in the pathogenesis of this condition is unclear. At present, the patient is in complete remission after an allogeneic stem cell transplantation procedure.

  16. Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia.

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    Bradstock, Kenneth F; Link, Emma; Di Iulio, Juliana; Szer, Jeff; Marlton, Paula; Wei, Andrew H; Enno, Arno; Schwarer, Anthony; Lewis, Ian D; D'Rozario, James; Coyle, Luke; Cull, Gavin; Campbell, Phillip; Leahy, Michael F; Hahn, Uwe; Cannell, Paul; Tiley, Campbell; Lowenthal, Ray M; Moore, John; Cartwright, Kimberly; Cunningham, Ilona; Taper, John; Grigg, Andrew; Roberts, Andrew W; Benson, Warwick; Hertzberg, Mark; Deveridge, Sandra; Rowlings, Philip; Mills, Anthony K; Gill, Devinder; Bardy, Peter; Campbell, Lynda; Seymour, John F

    2017-05-20

    Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m 2 daily for 5 days, etoposide 75 mg/m 2 daily for 5 days, and idarubicin 9 mg/m 2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in

  17. Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy.

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    Sander, Frida Ewald; Nilsson, Malin; Rydström, Anna; Aurelius, Johan; Riise, Rebecca E; Movitz, Charlotta; Bernson, Elin; Kiffin, Roberta; Ståhlberg, Anders; Brune, Mats; Foà, Robin; Hellstrand, Kristoffer; Thorén, Fredrik B; Martner, Anna

    2017-11-01

    Regulatory T cells (T regs ) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3 + CD25 high CD4 + T regs during immunotherapy and to determine the potential impact of T regs on relapse risk and survival. We observed a pronounced increase in T reg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating T regs resembled thymic-derived natural T regs (nT regs ), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by T reg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of T reg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of T regs in later treatment cycles and a short T reg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive T regs that may be targeted for improved anti-leukemic efficiency.

  18. High Risk of Hepatitis B Reactivation among Patients with Acute Myeloid Leukemia

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    Chen, Chien-Yuan; Huang, Sheng-Yi; Cheng, Aristine; Chou, Wen-Chien; Yao, Ming; Tang, Jih-Luh; Tsay, Woei; Sheng, Wang-Huei; Tien, Hwei-Fang

    2015-01-01

    Background Hepatitis B virus (HBV) infections are common and associated with significant morbidity and mortality in cancer patients. However, the incidence and risk factors of HBV reactivation in patients with acute myeloid leukemia (AML) are rarely investigated. Methods AML patients followed-up at the National Taiwan University Hospital between 2006 and 2012 were analyzed. The clinical characteristics and laboratory data were retrospectively reviewed. Results Four hundred and ninety patients comprising 265 men and 225 women were studied. The median age was 52 years (range, 18 - 94). Chronic HBV carriage was documented at the time of leukemia diagnosis in 57 (11.6%) patients. Forty-six (80.7%) of the 57 HBV carriers received prophylaxis with anti-HBV agents. Sixteen HBV carriers (28.1%) developed hepatitis B reactivation during or after chemotherapy, including 7 patients who had discontinued antiviral therapy. The incidence of hepatitis B reactivation among AML patients with HBV carriage was 9.5 per 100 person-years. Prophylaxis with anti-HBV agents significantly decreased the risk of hepatitis B reactivation among HBV carriers (13% vs. 61%, pHBcAb experienced hepatitis B reactivation and lost their protective anti-HBsAb. Multivariate analysis revealed that diabetes mellitus (p=0.008, odds ratio (OR) = 2.841, 95% confident interval (CI): 0.985-8.193) and carriage of HBsAg (p<0.001, OR=36.878, 95% CI: 11.770-115.547) were independent risk factors for hepatitis B reactivation in AML patients. Conclusions Hepatitis B reactivation is not uncommon in the HBsAg positive AML patients. Prophylaxis with anti-HBV agent significantly decreased the risk of hepatitis B reactivation. PMID:25973905

  19. High Risk of Hepatitis B Reactivation among Patients with Acute Myeloid Leukemia.

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    Chien-Yuan Chen

    Full Text Available Hepatitis B virus (HBV infections are common and associated with significant morbidity and mortality in cancer patients. However, the incidence and risk factors of HBV reactivation in patients with acute myeloid leukemia (AML are rarely investigated.AML patients followed-up at the National Taiwan University Hospital between 2006 and 2012 were analyzed. The clinical characteristics and laboratory data were retrospectively reviewed.Four hundred and ninety patients comprising 265 men and 225 women were studied. The median age was 52 years (range, 18 - 94. Chronic HBV carriage was documented at the time of leukemia diagnosis in 57 (11.6% patients. Forty-six (80.7% of the 57 HBV carriers received prophylaxis with anti-HBV agents. Sixteen HBV carriers (28.1% developed hepatitis B reactivation during or after chemotherapy, including 7 patients who had discontinued antiviral therapy. The incidence of hepatitis B reactivation among AML patients with HBV carriage was 9.5 per 100 person-years. Prophylaxis with anti-HBV agents significantly decreased the risk of hepatitis B reactivation among HBV carriers (13% vs. 61%, p<0.001. Four (2.8% of 142 patients with initial positive anti-HBsAb and anti-HBcAb experienced hepatitis B reactivation and lost their protective anti-HBsAb. Multivariate analysis revealed that diabetes mellitus (p=0.008, odds ratio (OR = 2.841, 95% confident interval (CI: 0.985-8.193 and carriage of HBsAg (p<0.001, OR=36.878, 95% CI: 11.770-115.547 were independent risk factors for hepatitis B reactivation in AML patients.Hepatitis B reactivation is not uncommon in the HBsAg positive AML patients. Prophylaxis with anti-HBV agent significantly decreased the risk of hepatitis B reactivation.

  20. Immune evasion in acute myeloid leukemia: current concepts and future directions.

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    Teague, Ryan M; Kline, Justin

    2013-08-27

    Immune responses generated against malignant cells have the potential to inhibit tumor growth, or even eliminate transformed cells before a tumor forms. However, immune tolerance mechanisms that normally protect healthy tissues from autoimmune damage pose a formidable barrier to the development of effective anti-tumor immunity. Because malignant cells are derived from self-tissues, the majority of defined tumor antigens are either shared or aberrantly expressed self-proteins. Eliciting productive T cell responses against such proteins is challenging, as most high-affinity, self-reactive T cells are purged during thymic selection. Some T cells capable of tumor antigen recognition escape thymic deletion, but are functionally inhibited by peripheral tolerance mechanisms which limit their ability to attack a developing malignancy. Alternatively, some tumors express antigens derived from mutated self-proteins, viral proteins or self proteins expressed only during embryonic development. These antigens are recognized by the immune system as foreign and could be recognized by a relatively large number of peripheral T cells. Even in this scenario, tumors evade otherwise effective T cell responses by employing potent immunosuppressive mechanisms within their local environment. In the setting for solid malignancies, such as melanoma, a growing number of putative immune evasion mechanisms have been characterized. However, acute myeloid leukemia (AML) is a systemic disease, and the pathways it exploits to subvert the host immune response may be quite different than those of a solid tumor. Much remains unknown regarding the immune escape mechanisms promoted by AML, and whether efforts to thwart tolerance may influence the progression of this disease. Here, we review current concepts of immune evasion in AML, and speculate how potentially effective immunotherapeutic strategies might be developed to reverse immune tolerance in leukemia patients in the future.

  1. Intracranial CNS Manifestations of Myeloid Sarcoma in Patients with Acute Myeloid Leukemia: Review of the Literature and Three Case Reports from the Author’s Institution

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    Gustavo M. Cervantes

    2015-05-01

    Full Text Available Myeloid sarcoma (MS of the central nervous system (CNS is a rare presentation of leukemic mass infiltration outside of the bone marrow. It may involve the subperiosteum and dura mater and, on rare occasions, can also invade the brain parenchyma. The disease is most commonly seen in children or young adults; however, it has been described in multiple age groups. MS can be seen in patients with acute myeloid leukemia (AML, chronic myeloid leukemia and other myeloproliferative disorders. This entity has the potential to be underdiagnosed if the MS appearance precedes the first diagnosis of leukemia. The main reason is that their appearance on CT and MRI has a broad differential diagnosis, and proper diagnosis of MS can only be made if the imaging findings are correlated with the clinical history and laboratory findings. Herein, we describe the intracranial CNS manifestations of MS in patients with AML on CT and MRI involving the brain and/or meninges. This study is based on a systematic review of the literature. In addition, three case reports from the author’s institution with AML and intracranial involvement of MS are included. Our aim is to enhance the awareness of this entity among both clinicians and radiologists.

  2. Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database.

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    Shukron, Ofir; Vainstein, Vladimir; Kündgen, Andrea; Germing, Ulrich; Agur, Zvia

    2012-09-01

    One-third of patients with myelodysplastic syndrome (MDS) progress to secondary acute myeloid leukemia (sAML), with its concomitant poor prognosis. Recently, multiple mutations have been identified in association with MDS-to-sAMLtransition, but it is still unclear whether all these mutations are necessary for transformation. If multiple independent mutations are required for the transformation, sAML risk should increase with time from MDS diagnosis. In contrast, if a single critical biological event determines sAML transformation; its risk should be constant in time elapsing from MDS diagnosis. To elucidate this question, we studied a database of 1079 patients with MDS. We classified patients according to the International Prognostic Scoring System (IPSS), using either the French-American-British (FAB) or the World Health Organization (WHO) criteria, and statistically analyzed the resulting transformation risk curves of each group. The risk of transformation after MDS diagnosis remained constant in time within three out of four risk groups, and in all four risk groups, when patients were classified according to FAB or to the WHO-determined criteria, respectively. Further subdivision by blast percentage or cytogenetics had no influence on this result. Our analysis suggests that a single random biological event leads to transformation to sAML, thus calling for the exclusion of time since MDS diagnosis from the clinical decision-making process. Copyright © 2012 Wiley Periodicals, Inc.

  3. Is it time to change conventional consolidation chemotherapy for acute myeloid leukemia in CR1?

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    Wolach, Ofir; Stone, Richard M

    2015-03-01

    Choosing the most appropriate postremission therapy (PRT) for a patient with acute myeloid leukemia (AML) in first complete remission remains a challenging task. Factors such as risk for disease relapse, nonrelapse mortality associated with different PRT approaches, donor availability, prospects for salvage should disease relapse, and patient preference all affect PRT choice. New genetic markers refine AML risk stratification and identify patients within the 'classical' risk groups who may benefit from transplant-based or chemotherapy-based PRT. The use of minimal residual disease in first remission to guide PRT choice and the application of novel, targeted therapies have the potential to alter PRT approaches across AML risk groups. The advent of alternative donor sources, use of reduced intensity regimens, and improved supportive care all affect the availability and safety of transplant-based PRT and challenge the relevance of the older legacy 'donor/no-donor' genetically randomized trials. Genetic risk assessment, monitoring of minimal residual disease in first remission, use of targeted agents, and the newer transplant strategies all have the potential to 'personalize' PRT choice in the AML patient. The clinical value of these novel interventions awaits validation in prospective, risk-adapted clinical trials.

  4. Expression of some ATP-binding cassette transporters in acute myeloid leukemia

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    Antonella Maria Salvia

    2017-12-01

    Full Text Available Hematopoietic cells express ATP binding cassette (ABC transporters in relation to different degrees of differentiation. One of the known multidrug resistance mechanisms in acute myeloid leukemia (AML is the overexpression of efflux pumps belonging to the superfamily of ABC transporters such as ABCB1, ABCG2 and ABCC1. Although several studies were carried out to correlate ABC transporters expression with drug resistance, little is known about their role as markers of diagnosis and progression of the disease. For this purpose we investigated the expression, by real-time PCR, of some ABC genes in bone marrow samples of AML patients at diagnosis and after induction therapy. At diagnosis, ABCG2 was always down-regulated, while an up regulated trend for ABCC1 was observed. After therapy the examined genes showed a different expression trend and approached the values of healthy subjects suggesting that this event could be considered as a marker of AML regression. The expression levels of some ABC transporters such as ABCC6, seems to be related to gender, age and to the presence of FLT3/ITD gene mutation.

  5. Synergistic interaction of Smac mimetic and IFNα to trigger apoptosis in acute myeloid leukemia cells.

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    Bake, Vanessa; Roesler, Stefanie; Eckhardt, Ines; Belz, Katharina; Fulda, Simone

    2014-12-28

    Therapeutic targeting of inhibitor of apoptosis (IAP) proteins by small-molecule inhibitors such as Smac mimetic is considered as a promising anticancer strategy to elicit apoptosis. Recent advances have renewed the interest in exploiting the antileukemic activity of interferon (IFN)α for the treatment of acute myeloid leukemia (AML). Here, we identify a novel synergistic interaction of the Smac mimetic BV6 and IFNα to trigger cell death in AML cells. Calculation of combination index (CI) confirms the synergism of BV6 and IFNα. In contrast to AML cells, no synergistic toxicity of BV6 and IFNα at equimolar concentrations is found against normal peripheral blood lymphocytes. BV6 and IFNα act in concert to stimulate expression of tumor necrosis factor (TNF)α and its secretion into the supernatant, thereby initiating an autocrine/paracrine TNFα/TNF receptor 1 (TNFR1) loop that drives cell death by BV6 and IFNα. Consistently, pharmacological inhibition of TNFα by the TNFα-blocking antibody Enbrel or genetic silencing of TNFR1 significantly reduces BV6/IFNα-induced cell death. In addition, BV6/IFNα-induced cell death depends on interferon regulatory factor (IRF)1, since RNA interference-imposed knockdown of IRF1 significantly rescues cell death. In conclusion, the identification of a novel synergistic antileukemic combination of Smac mimetic and IFNα has important implications for the development of innovative treatment strategies in AML. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Clinical significance of P53 and Bcl-2 in acute myeloid leukemia patients of Eastern India

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    Geetaram Sahu

    2011-11-01

    Full Text Available The frequency of p53 and Bcl-2 protein expression in 100 newly diagnosed and 10 relapsed acute myeloid leukemia (AML patients was analyzed by immunocytochemistry (ICC. The Kaplan-Meier method was used for univariate and multivariate statistical analysis to assess the relationship between p53, Bcl-2 and clinico-hematologic feature with respect to overall survival (OS using SPSS statistical software. No statistical significance was found in univariate analysis (P=0.60. However, when the subgroups of patients (+1, +2, +3 and +4 were compared, expression of p53 and Bcl-2 protein (1-10%, 11- 30%, 31-50% and >50% was statistically significant (P<0.05. However, in multivariate analysis, p53, immunopositivity was independently associated with a shorter overall survival (OS (P=0.038 while Bcl-2 immunopositivity was associated with longer overall survival (OS (P=0.002. Our finding shows that p53 and Bcl-2 protein overexpression is a strong indicator of response to chemotherapy and overall survival. This study reports for the first time AML in patients from Eastern India.

  7. Monosomal karyotype is not a predictor of dismal outcome in childhood de novo acute myeloid leukemia.

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    Lee, Na Hee; Choi, Young Bae; Yi, Eun-Sang; Lee, Soo Hyun; Kim, Hee-Jin; Lee, Ji Won; Sung, Ki Woong; Koo, Hong Hoe; Yoo, Keon Hee

    2016-11-01

    Monosomal karyotype (MK) is known as a far end of the unfavorable cytogenetics in adult acute myeloid leukemia (AML), while available data in childhood AML is scarce. In this study, we investigated the prevalence and prognostic value of MK with retrospectively analyzed 119 patients newly diagnosed with childhood de novo AML. Ten patients (8.4%) revealed to have MK. All MK-positive (MK(+)) AML were associated with complex cytogenetic abnormalities and belonged to the cytogenetic adverse-risk group. Nine of MK(+) patients (90%) achieved complete remission. The event-free survival (EFS) and overall survival (OS) of MK(+) adverse group were comparable to the ESF and OS of MK-negative non-adverse group (EFS 60.0±15.5% vs 59.0±5.1%, P=0.925; OS 70.0±14.5% vs 58.1±5.3%, P=0.696). In multivariate analysis, MK was not an independent adverse prognostic factor for EFS (hazard ratio 0.45, 95% C.I. 0.13-1.50, P=0.194). In addition, 7 of 9 MK(+) patients who received allogeneic hematopoietic stem cell transplantation (HSCT) survived event-free, with a median follow-up of 64 months. In conclusion, MK did not act as an adverse prognostic factor in childhood de novo AML. Allogeneic HSCT might have contributed to the excellent outcome of MK(+) childhood de novo AML. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Mitochondrial Profiling of Acute Myeloid Leukemia in the Assessment of Response to Apoptosis Modulating Drugs.

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    Ishizawa, Jo; Kojima, Kensuke; McQueen, Teresa; Ruvolo, Vivian; Chachad, Dhruv; Nogueras-Gonzalez, Graciela M; Huang, Xuelin; Pierceall, William E; Dettman, E J; Cardone, Michael H; Shacham, Sharon; Konopleva, Marina; Andreeff, Michael

    2015-01-01

    BH3 profiling measures the propensity of transformed cells to undergo intrinsic apoptosis and is determined by exposing cells to BH3-mimicking peptides. We hypothesized that basal levels of prosurvival BCL-2 family proteins may modulate the predictive power of BH3 profiling and termed it mitochondrial profiling. We investigated the correlation between cell sensitivity to apoptogenic agents and mitochondrial profiling, using a panel of acute myeloid leukemias induced to undergo apoptosis by exposure to cytarabine, the BH3 mimetic ABT-199, the MDM2 inhibitor Nutlin-3a, or the CRM1 inhibitor KPT-330. We found that the apoptogenic efficacies of ABT-199 and cytarabine correlated well with BH3 profiling reflecting BCL2, but not BCL-XL or MCL-1 dependence. Baseline BCL-2 protein expression analysis increased the ability of BH3 profiling to predict resistance mediated by MCL-1. By utilizing engineered cells with overexpression or knockdown of BCL-2 family proteins, Ara-C was found to be independent, while ABT-199 was dependent on BCL-XL. BCL-2 and BCL-XL overexpression mediated resistance to KPT-330 which was not reflected in the BH3 profiling assay, or in baseline BCL-2 protein levels. In conclusion, mitochondrial profiling, the combination of BH3 profiling and prosurvival BCL-2 family protein analysis, represents an improved approach to predict efficacy of diverse agents in AML and may have utility in the design of more effective drug combinations.

  9. Prognostic significance of leukopenia at the time of diagnosis in acute myeloid leukemia.

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    Arellano, Martha; Bernal-Mizrachi, Leon; Pan, Lin; Tighiouart, Mourad; Souza, Liliana; Guo, Xiangxue; McLemore, Morgan; Lima, Lisa; Sunay, Susan; Heffner, Leonard T; Chen, Zhengjia; Chen, Georgia Zhou; Langston, Amelia; Winton, Elliott; Khoury, H Jean

    2011-10-01

    We investigated the clinical significance of leukopenia at the time of diagnosis in a cohort of 225 patients with newly diagnosed acute myeloid leukemia (AML) at a single institution. Leukocyte count was treated as a continuous variable and, using a receiver operating characteristic curve (ROC), a cutoff of 3,600/μL had the best sensitivity and specificity for remission (complete remission [CR]), relapse-free survival [RFS], and overall survival [OS]). In a multivariable model, leukopenia at diagnosis had no effects on CR (hazard ratio [HR] = 2.02; confidence interval [CI], 0.9-4.3; P = .07), RFS (HR = 0.93; CI, 0.5-1.5; P = .8), or OS (HR = 1.05; CI, 0.7-1.5; P = .7). No differential expression of cell surface molecules (CD34, c-Kit, CXCR4, PECAM, VLA2, VLA-, VLA4, VLA5, and FLT3) was observed on simultaneously obtained marrow and blood blasts in the high- vs. low-leukocyte groups. We conclude that leukopenia at diagnosis carries no prognostic significance in AML. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Preservation Method and Phosphate Buffered Saline Washing Affect the Acute Myeloid Leukemia Proteome

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    Rebecca Wangen

    2018-01-01

    Full Text Available Acute myeloid leukemia (AML primary cells can be isolated from peripheral blood, suspended with media containing bovine serum and cryoprotectant, and stored in liquid nitrogen before being processed for proteomic analysis by mass spectrometry (MS. The presence of bovine serum and human blood proteins in AML samples can hamper the identifications of proteins, and thereby reduce the proteome coverage of the study. Herein, we have established the effect of phosphate buffered saline (PBS washing on AML patient samples stored in media. Although PBS washes effectively removed serum and blood contaminants, the saline wash resulted in cell burst and remarkable protein material loss. We also compared different methods to preserve the AML proteome from THP-1 and Molm-13 cell lines before MS analysis: (1 stored in media containing bovine serum and dimethyl sulfoxide (DMSO; (2 stored as dried cell pellets; and (3 stored as cell lysates in 4% sodium dodecyl sulfate (SDS. MS analysis of differently preserved AML cell samples shows that preservation with DMSO produce a high number of fragile cells that will burst during freezing and thawing. Our studies encourage the use of alternative preservation methods for future MS analysis of the AML proteome.

  11. Autoantibodies Against Carbonic Anhydrase I and II in Patients with Acute Myeloid Leukemia

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    Ahmet Menteşe

    2017-12-01

    Full Text Available Objective: Cancer, one of the principal causes of death, is a global social health problem. Autoantibodies developed against the organism’s self-antigens are detected in the sera of subjects with cancer. In recent years carbonic anhydrase (CA I and II autoantibodies have been shown in some autoimmune diseases and carcinomas, but the mechanisms underlying this immune response have not yet been explained. The aim of this study was to evaluate CA I and II autoantibodies in patients with acute myeloid leukemia (AML and to provide a novel perspective regarding the autoimmune basis of the disease. Materials and Methods: Anti-CA I and II antibody levels were investigated using ELISA in serum samples from 30 patients with AML and 30 healthy peers. Results: Anti-CA I and II antibody titers in the AML group were significantly higher compared with the control group (p=0.0001 and 0.018, respectively. A strong positive correlation was also determined between titers of anti-CA I and II antibodies (r=0.613, p=0.0001. Conclusion: Our results suggest that these autoantibodies may be involved in the pathogenesis of AML. More extensive studies are now needed to reveal the entire mechanism.

  12. An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

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    Lopez, Sophie; Voisset, Edwige; Tisserand, Julie C.; Mosca, Cyndie; Prebet, Thomas; Santamaria, David; Dubreuil, Patrice; Sepulveda, Paulo De

    2016-01-01

    CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6−/− mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations. PMID:27323399

  13. Outpatient management following intensive induction or salvage chemotherapy for acute myeloid leukemia.

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    Walter, Roland B; Taylor, Lenise R; Gardner, Kelda M; Dorcy, Kathleen Shannon; Vaughn, Jennifer E; Estey, Elihu H

    2013-01-01

    Adults with newly diagnosed or relapsed acute myeloid leukemia (AML) commonly receive intensive chemotherapy to achieve disease remission. In the United States and many other countries, it is standard practice that these patients remain hospitalized "preemptively" until blood count recovery, owing to the risk for overwhelming infections and bleeding during pancytopenia. This care policy requires hospitalization for an average of 3 to 4 weeks after completion of chemotherapy. However, highly effective oral prophylactic antimicrobials are now available, and transfusion support of outpatients has become routine in recent years. As a result, the care of patients with hematologic malignancies treated with intensive modalities is increasingly shifting from inpatient to outpatient settings. Benefits of this shift could include the reduced need for medical resources (eg, transfusions or intravenous antimicrobial therapy), improved quality of life (QOL), decreased rates of nosocomial infections, and lower costs. Increasing evidence indicates that select AML patients undergoing intensive remission induction or salvage chemotherapy can be discharged early after completion of chemotherapy and followed closely in a well-equipped outpatient facility in a safe and costeffective manner. Further demonstration that the current approach of preemptive hospitalization is medically unjustified, economically more burdensome, and adversely affects health-related QOL would very likely change the management of these patients throughout this country and elsewhere, resulting in the establishment of a new standard practice that improves cancer care.

  14. MYST3/CREBBP Rearranged Acute Myeloid Leukemia after Adjuvant Chemotherapy for Breast Cancer

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    Arjun Gupta

    2014-01-01

    Full Text Available Although rare, clinicians and patients must be aware that therapy related malignancies, specifically acute myeloid leukemia (AML, can occur as a complication of adjuvant chemotherapy for breast cancer. Vigilance for signs and symptoms is appropriate. AML with t (8;16 is a specific translocation leading to formation of a fusion protein (MYST3/CREBBP. The MYST3/CREBBP AML tends to develop within 2 years of adjuvant chemotherapy, especially for breast cancer, without preceding myelodysplasia. It usually presents with disseminated intravascular coagulation and osteolytic lesions and has a poor prognosis despite aggressive resuscitation and therapy. With the increasing use of adjuvant chemotherapy for breast cancer, we are seeing a definite increase in the incidence of therapy related myelodysplastic syndromes and AML. One must keep this complication in mind while counseling and following up breast cancer patients who have received adjuvant chemotherapy. New osteolytic bone lesions in a patient with history of breast cancer do not necessarily mean metastatic disease and should be fully evaluated.

  15. [Identification of novel pathogenic gene mutations in pediatric acute myeloid leukemia by whole-exome resequencing].

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    Shiba, Norio

    2015-12-01

    A new class of gene mutations, identified in the pathogenesis of adult acute myeloid leukemia (AML), includes DNMT3A, IDH1/2, TET2 and EZH2. However, these mutations are rare in pediatric AML cases, indicating that pathogeneses differ between adult and pediatric forms of AML. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across entire genomes or proteincoding sequences. In order to reveal a complete registry of gene mutations, we performed whole exome resequencing of paired tumor-normal specimens from 19 pediatric AML cases using Illumina HiSeq 2000. In total, 80 somatic mutations or 4.2 mutations per sample were identified. Many of the recurrent mutations identified in this study involved previously reported targets in AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1 and EZH2. On the other hand, several genes were newly identified in the current study, including BCORL1 and major cohesin components such as SMC3 and RAD21. Whole exome resequencing revealed a complex array of gene mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that could be discriminated from its adult counterpart, in terms of the spectrum of gene mutations.

  16. Detection of prognostic methylation markers by methylC-capture sequencing in acute myeloid leukemia.

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    Li, Yan; Zhao, Hongmei; Xu, Qingyu; Lv, Na; Jing, Yu; Wang, Lili; Wang, Xiaowen; Guo, Jing; Zhou, Lei; Liu, Jing; Chen, Guofeng; Chen, Chongjian; Li, Yonghui; Yu, Li

    2017-12-15

    Clinical and genetic features incompletely predict outcome in acute myeloid leukemia (AML). The value of clinical methylation assays for prognostic markers has not been extensively explored. We assess the prognostic implications of methylC-capture sequencing (MCC-Seq) in patients with de novo AML by integrating DNA methylation and genetic risk stratification. MCC-Seq assessed DNA methylation level in 44 samples. The differentially methylated regions associated with prognostic genetic information were identified. The selected prognostic DNA methylation markers were independently validated in two sets. MCC-Seq exhibited good performance in AML patients. A panel of 12 differentially methylated genes was identified with promoter hyper-differentially methylated regions associated with the outcome. Compared with a low M-value, a high M-value was associated with failure to achieve complete remission ( p = 0.024), increased hazard for disease-free survival in the study set ( p = 0.039) and poor overall survival in The Cancer Genome Atlas set ( p = 0.038). Hematopoietic stem cell transplantation and survival outcomes were not adversely affected by a high M-value ( p = 0.271). Our study establishes that MCC-Seq is a stable, reproducible, and cost-effective methylation assay in AML. A 12-gene M-value encompassing epigenetic and genetic prognostic information represented a valid prognostic marker for patients with AML.

  17. An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia

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    Zhisheng Her

    2017-10-01

    Full Text Available Abstract Background Xenotransplantation of patient-derived AML (acute myeloid leukemia cells in NOD-scid Il2rγ null (NSG mice is the method of choice for evaluating this human hematologic malignancy. However, existing models constructed using intravenous injection in adult or newborn NSG mice have inferior engraftment efficiency, poor peripheral blood engraftment, or are difficult to construct. Methods Here, we describe an improved AML xenograft model where primary human AML cells were injected into NSG newborn pups intrahepatically. Results Introduction of primary cells from AML patients resulted in high levels of engraftment in peripheral blood, spleen, and bone marrow (BM of recipient mice. The phenotype of engrafted AML cells remained unaltered during serial transplantation. The mice developed features that are consistent with human AML including spleen enlargement and infiltration of AML cells into multiple organs. Importantly, we demonstrated that although leukemic stem cell activity is enriched and mediated by CD34+CD117+ subpopulation, CD34+CD117− subpopulation can acquire CD34+CD117+ phenotype through de-differentiation. Lastly, we evaluated the therapeutic potential of Sorafenib and Regorafenib in this AML model and found that periphery and spleen AML cells are sensitive to these treatments, whereas BM provides a protective environment to AML. Conclusions Collectively, our improved model is robust, easy-to-construct, and reliable for pre-clinical AML studies.

  18. Minimal Residual Disease Diagnostics and Chimerism in the Post-Transplant Period in Acute Myeloid Leukemia

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    Ulrike Bacher

    2011-01-01

    Full Text Available In acute myeloid leukemia (AML, the selection of poor-risk patients for allogeneic hematopoietic stem cell transplantation (HSCT is associated with rather high post-transplant relapse rates. As immunotherapeutic intervention is considered to be more effective before the cytomorphologic manifestation of relapse, post-transplant monitoring gains increasing attention in stem cell recipients with a previous diagnosis of AML. Different methods for detection of chimerism (e.g., microsatellite analysis or quantitative real-time PCR are available to quantify the ratio of donor and recipient cells in the post-transplant period. Various studies demonstrated the potential use of mixed chimerism kinetics to predict relapse of the AML. CD34+-specific chimerism is associated with a higher specificity of chimerism analysis. Nevertheless, a decrease of donor cells can have other causes as well. Therefore, efforts continue to introduce minimal residual disease (MRD monitoring based on molecular mutations in the post-transplant period. The NPM1 (nucleophosmin mutations can be monitored by sensitive quantitative real-time PCR in subsets of stem cell recipients with AML, but for approximately 20% of patients, suitable molecular mutations for post-transplant MRD monitoring are not available so far. This emphasizes the need for an expansion of the panel of MRD markers in the transplant setting.

  19. HLA-G expression on blasts and tolerogenic cells in patients affected by acute myeloid leukemia.

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    Locafaro, Grazia; Amodio, Giada; Tomasoni, Daniela; Tresoldi, Cristina; Ciceri, Fabio; Gregori, Silvia

    2014-01-01

    Human Leukocyte Antigen-G (HLA-G) contributes to cancer cell immune escape from host antitumor responses. The clinical relevance of HLA-G in several malignancies has been reported. However, the role of HLA-G expression and functions in Acute Myeloid Leukemia (AML) is still controversial. Our group identified a subset of tolerogenic dendritic cells, DC-10 that express HLA-G and secrete IL-10. DC-10 are present in the peripheral blood and are essential in promoting and maintaining tolerance via the induction of adaptive T regulatory (Treg) cells. We investigated HLA-G expression on blasts and the presence of HLA-G-expressing DC-10 and CD4(+) T cells in the peripheral blood of AML patients at diagnosis. Moreover, we explored the possible influence of the 3' untranslated region (3'UTR) of HLA-G, which has been associated with HLA-G expression, on AML susceptibility. Results showed that HLA-G-expressing DC-10 and CD4(+) T cells are highly represented in AML patients with HLA-G positive blasts. None of the HLA-G variation sites evaluated was associated with AML susceptibility. This is the first report describing HLA-G-expressing DC-10 and CD4(+) T cells in AML patients, suggesting that they may represent a strategy by which leukemic cells escape the host's immune system. Further studies on larger populations are required to verify our findings.

  20. Regulatory T cells-derived IL-35 promotes the growth of adult acute myeloid leukemia blasts.

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    Tao, Qianshan; Pan, Ying; Wang, Yiping; Wang, Huiping; Xiong, Shudao; Li, Qing; Wang, Jia; Tao, Lili; Wang, Zhitao; Wu, Fan; Zhang, Rui; Zhai, Zhimin

    2015-11-15

    Tumor immune escape mechanism mediated by CD4+CD25+regulatory T cells (Tregs) is a key factor in the pathogenesis of acute myeloid leukemia (AML). IL-35, as a novel inhibitory cytokine, is produced by Tregs specially and regulates functions of Tregs in murine. However, IL-35 expression of Tregs in human is still disputed, and its role in AML is yet to be elucidated. In this study, we found that IL-35 was expressed highly in peripheral blood plasma of adult patients with AML and significantly correlated with the clinical stages of malignancy. Tregs-derived from adult AML patients produced IL-35 in a stimulation-dependent manner. IL-35 promoted AML blasts immune escape by expanding Tregs and inhibiting CD4+CD25-effector T cells (Teffs). Furthermore, IL-35 directly promoted the proliferation of AML blasts and reduced the apoptosis of AML blasts. Together, our study demonstrates that IL-35-derived from Tregs promotes the growth of adult AML blasts, suggesting that IL-35 has an important role in the pathogenesis of AML. © 2015 UICC.

  1. HLA-G Expression on Blasts and Tolerogenic Cells in Patients Affected by Acute Myeloid Leukemia

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    Grazia Locafaro

    2014-01-01

    Full Text Available Human Leukocyte Antigen-G (HLA-G contributes to cancer cell immune escape from host antitumor responses. The clinical relevance of HLA-G in several malignancies has been reported. However, the role of HLA-G expression and functions in Acute Myeloid Leukemia (AML is still controversial. Our group identified a subset of tolerogenic dendritic cells, DC-10 that express HLA-G and secrete IL-10. DC-10 are present in the peripheral blood and are essential in promoting and maintaining tolerance via the induction of adaptive T regulatory (Treg cells. We investigated HLA-G expression on blasts and the presence of HLA-G-expressing DC-10 and CD4+ T cells in the peripheral blood of AML patients at diagnosis. Moreover, we explored the possible influence of the 3′ untranslated region (3′UTR of HLA-G, which has been associated with HLA-G expression, on AML susceptibility. Results showed that HLA-G-expressing DC-10 and CD4+ T cells are highly represented in AML patients with HLA-G positive blasts. None of the HLA-G variation sites evaluated was associated with AML susceptibility. This is the first report describing HLA-G-expressing DC-10 and CD4+ T cells in AML patients, suggesting that they may represent a strategy by which leukemic cells escape the host’s immune system. Further studies on larger populations are required to verify our findings.

  2. GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells

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    Koichi R. Katsumura

    2016-08-01

    Full Text Available The master regulatory transcription factor GATA-2 triggers hematopoietic stem and progenitor cell generation. GATA2 haploinsufficiency is implicated in myelodysplastic syndrome (MDS and acute myeloid leukemia (AML, and GATA2 overexpression portends a poor prognosis for AML. However, the constituents of the GATA-2-dependent genetic network mediating pathogenesis are unknown. We described a p38-dependent mechanism that phosphorylates GATA-2 and increases GATA-2 target gene activation. We demonstrate that this mechanism establishes a growth-promoting chemokine/cytokine circuit in AML cells. p38/ERK-dependent GATA-2 phosphorylation facilitated positive autoregulation of GATA2 transcription and expression of target genes, including IL1B and CXCL2. IL-1β and CXCL2 enhanced GATA-2 phosphorylation, which increased GATA-2-mediated transcriptional activation. p38/ERK-GATA-2 stimulated AML cell proliferation via CXCL2 induction. As GATA2 mRNA correlated with IL1B and CXCL2 mRNAs in AML-M5 and high expression of these genes predicted poor prognosis of cytogenetically normal AML, we propose that the circuit is functionally important in specific AML contexts.

  3. Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia.

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    Swords, Ronan T; Kelly, Kevin R; Smith, Peter G; Garnsey, James J; Mahalingam, Devalingam; Medina, Ernest; Oberheu, Kelli; Padmanabhan, Swaminathan; O'Dwyer, Michael; Nawrocki, Steffan T; Giles, Francis J; Carew, Jennifer S

    2010-05-06

    NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappaB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.

  4. Cytogenetic profiles of 2806 patients with acute myeloid leukemia-a retrospective multicenter nationwide study.

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    Byun, Ja Min; Kim, Young Jin; Yoon, Hwi-Joong; Kim, Si-Young; Kim, Hee-Je; Yoon, Jaeho; Min, Yoo Hong; Cheong, Jun-Won; Park, Jinny; Lee, Jae Hoon; Hong, Dae Sik; Park, Seong Kyu; Kim, Hyeoung-Joon; Ahn, Jae-Sook; Shin, Ho-Jin; Chung, Joo Seop; Lee, Won Sik; Lee, Sang Min; Park, Yong; Kim, Byung Soo; Lee, Je-Hwan; Lee, Kyoo-Hyung; Jung, Chul Won; Jang, Jun Ho; Min, Woo-Sung; Park, Tae Sung

    2016-08-01

    The cytogenetic and molecular data is recognized as the most valuable prognostic factor in acute myeloid leukemia (AML). Our aim was to systemically analyze the cytogenetics of Korean AML patients and to compare the cytogenetic profiles of various races to identify possible geographic heterogeneity. We retrospectively reviewed medical records of 2806 AML patients diagnosed at 11 tertiary teaching hospitals in Korea between January 2007 and December 2011. The most common recurrent chromosomal abnormality was t(8;21) (8.8 %, 238/2717), but t(15;17) showed an almost same number (8.6 %,235/2717). Among de novo AML, the most frequent aberrations were t(15;17), observed in 229 (10.7 %). The most common French-American-British (FAB) classification type was M2 (32.2 %), and recurrent cytogenetic abnormalities correlated with the FAB subtypes. Among 283 secondary AML cases, myelodysplastic syndrome was the most common predisposing factor. About 67.1 % of the secondary AML cases were associated with chromosomal aberrations, and chromosome 7 abnormalities (n = 45, 15.9 %) were most common. The incidence of FLT3 internal tandem duplication mutation was relatively low at 15 %. Our study reports certain similarities and differences in comparison to previous reports. Such discrepancies call for extensive epidemiological studies to clarify the role of genetic as well as geographic heterogeneity in the pathogenesis of AML.

  5. The prognostic implication of SRSF2 mutations in Chinese patients with acute myeloid leukemia.

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    Yang, Jing; Yao, Dong-Ming; Ma, Ji-Chun; Yang, Lei; Guo, Hong; Wen, Xiang-Mei; Xiao, Gao-Fei; Qian, Zhen; Lin, Jiang; Qian, Jun

    2016-08-01

    Recently, somatic mutations in SRSF2 gene have been discovered in a proportion of hematologic malignancies including acute myeloid leukemia (AML). This study was aimed to investigate SRSF2 mutations in Chinese AML patients. High-resolution melting analysis (HRMA) was developed to screen SRSF2 mutations in 249 cases with AML, and then direct DNA sequencing was used to verify the results of HRMA. In this study, 3.6 % (9/249) of Chinese AML patients were found with heterozygous SRSF2 mutations. Patients with SRSF2 mutations were older than those with wild-type SRSF2 (P = 0.014). No differences in the sex, blood parameters, French-American-British classification (FAB) subtypes, and karyotypes were observed between AML patients with and without SRSF2 mutations. Although the overall survival (OS) of SRSF2-mutated patients was inferior to those without mutations in both whole AML patients (median 4 vs. 11 months, respectively; P = 0.006) and cytogenetically normal patients (median 2 vs. 12 months, respectively; P = 0.008), multiple analysis disclosed that SRSF2 mutation was not an independent prognostic factor in AML patients. These results suggest that SRSF2 mutation occurs at a low frequency in aged AML patients and might not be associated with adverse prognosis in Chinese AML patients.

  6. Resveratrol Downregulates Interleukin-6-Stimulated Sonic Hedgehog Signaling in Human Acute Myeloid Leukemia

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    Yu-Chieh Su

    2013-01-01

    Full Text Available IL-6 and sonic hedgehog (Shh signaling molecules are considered to maintain the growth of cancer stem cells (CSCs. Resveratrol, an important integrant in traditional Chinese medicine, possesses certain antitumor effects. However, the mechanisms on regulating acute myeloid leukemia (AML are unclear. This study first used human subjects to demonstrate that the plasma levels of IL-6 and IL-1β in AML patients were higher and lower, respectively, than healthy donors. The expression of Shh preproproteins, and C- and N-terminal Shh peptides increased in bone marrow and peripheral blood mononuclear cells isolated from AML patients, and the plasma N-Shh secretion was greater. To further clarify the effect of IL-6 and resveratrol in Shh signaling, human AML HL-60 cells were tested. IL-6 upregulated Shh and Gli-1 expression and was accompanied by an increase of cell viability. Resveratrol significantly decreased CSC-related Shh expression, Gli-1 nuclear translocation, and cell viability in IL-6-treated HL-60 cells and had synergistic effect with Shh inhibitor cyclopamine on inhibiting cell growth. Conclusions. IL-6 stimulated the growth of AML cells through Shh signaling, and this effect might be blocked by resveratrol. Further investigations of Shh as a prognostic marker and resveratrol as a therapeutic drug target to CSCs in AML are surely warranted.

  7. The plasma lipidome in acute myeloid leukemia at diagnosis in relation to clinical disease features.

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    Pabst, Thomas; Kortz, Linda; Fiedler, Georg M; Ceglarek, Uta; Idle, Jeffrey R; Beyoğlu, Diren

    2017-06-01

    Early studies established that certain lipids were lower in acute myeloid leukemia (AML) cells than normal leukocytes. Because lipids are now known to play an important role in cell signaling and regulation of homeostasis, and are often perturbed in malignancies, we undertook a comprehensive lipidomic survey of plasma from AML patients at time of diagnosis and also healthy blood donors. Plasma lipid profiles were measured using three mass spectrometry platforms in 20 AML patients and 20 healthy blood donors. Data were collected on total cholesterol and fatty acids, fatty acid amides, glycerolipids, phospholipids, sphingolipids, cholesterol esters, coenzyme Q10 and eicosanoids. We observed a depletion of plasma total fatty acids and cholesterol, but an increase in certain free fatty acids with the observed decline in sphingolipids, phosphocholines, triglycerides and cholesterol esters probably driven by enhanced fatty acid oxidation in AML cells. Arachidonic acid and precursors were elevated in AML, particularly in patients with high bone marrow (BM) or peripheral blasts and unfavorable prognostic risk. PGF2α was also elevated, in patients with low BM or peripheral blasts and with a favorable prognostic risk. A broad panoply of lipid classes is altered in AML plasma, pointing to disturbances of several lipid metabolic interconversions, in particular in relation to blast cell counts and prognostic risk. These data indicate potential roles played by lipids in AML heterogeneity and disease outcome. Enhanced catabolism of several lipid classes increases prognostic risk while plasma PGF2α may be a marker for reduced prognostic risk in AML.

  8. Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing.

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    Andrew E O Hughes

    2014-07-01

    Full Text Available Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells.

  9. Wilms Tumor 1 Gene Mutations in Patients with Cytogenetically Normal Acute Myeloid Leukemia

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    Aref, Salah; Sharawy, Solafa El; Sabry, Mohamed; Azmy, Emad; Raouf, Dalia Abdel; Menshawy, Nadia El

    2014-01-01

    Objective: This study aimed to assess the prognostic impact of Wilms tumor 1 (WT1) mutations in cytogenetically normal acute myeloid leukemia (CN-AML) among Egyptian patients. Materials and Methods: Exons 1, 2, 3, 7, 8, and 9 of WT1 were screened for mutations in samples from 82 CN-AML patients out of 203 newly diagnosed AML patients, of age ranging from 21 to 74 years, using high-resolution capillary electrophoresis. Results: Eleven patients out of 82 (13.41%) harbored WT1 mutations. Mutations were detected in exon 7 (n=7), exon 9 (n=2), exon 8 (n=1), and exon 3 (n=1), but not in exons 1 or 2. There was no statistically significant difference between the WT1 mutants and wild types as regards age, sex, French-American-British subtypes, and the prevalence of success of induction remission therapy (p=0.966; 28.6% vs. 29.3%). Patients with WT1 mutations had overall survival lower than patients with the wild type (HR=1.38; 95% CI 4.79-6.86; p=0.004). Conclusion: CN-AML patients with WT1 mutations have poor clinical outcome. We recommend molecular testing for WT1 mutations in patients with CN-AML at diagnosis in order to improve risk stratification of those patients. PMID:25035671

  10. Wilms Tumor 1 Gene Mutations in Patients with Cytogenetically Normal Acute Myeloid Leukemia

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    Salah Aref

    2014-03-01

    Full Text Available OBJECTIVE: This study aimed to assess the prognostic impact of Wilms tumor 1 (WT1 mutations in cytogenetically normal acute myeloid leukemia (CN-AML among Egyptian patients. METHODS: Exons 1, 2, 3, 7, 8, and 9 of WT1 were screened for mutations in samples from 82 CNAML patients out of 203 newly diagnosed AML patients, of age ranging from 21 to 74 years, using high-resolution capillary electrophoresis. RESULTS: Eleven patients out of 82 (13.41% harbored WT1 mutations. Mutations were detected in exon 7 (n=7, exon 9 (n=2, exon 8 (n=1, and exon 3 (n=1, but not in exons 1 or 2. There was no statistically significant difference between the WT1 mutants and wild types as regards age, sex, French-American-British subtypes, and the prevalence of success of induction remission therapy (p=0.966; 28.6% vs. 29.3%. Patients with WT1 mutations had overall survival lower than patients with the wild type (HR=1.38; 95% CI 4.79-6.86; p=0.004. CONCLUSION: CN-AML patients with WT1 mutations have poor clinical outcome. We recommend molecular testing for WT1 mutations in patients with CN-AML at diagnosis in order to improve risk stratification of those patients.

  11. Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

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    Babushok, Daria V.; Bessler, Monica; Olson, Timothy S.

    2016-01-01

    Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes. PMID:26693794

  12. Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells.

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    Luca A Petruccelli

    Full Text Available Histone deacetylase inhibitors (HDACi are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clinically relevant concentrations, vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Additionally, AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a reduction in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre-treatment with the antioxidant N-acetyl cysteine (NAC reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents.

  13. Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights

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    Zhu Xiongpeng

    2010-04-01

    Full Text Available Abstract Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML. However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine, FLT3 inhibitor (sorafenib, farnesyl-transferase inhibitor (tipifarnib, histone deacetylase inhibitor (vorinostat, lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine, were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421 from the 2009 ASH annual meeting.

  14. Vorinostat Induces Reactive Oxygen Species and DNA Damage in Acute Myeloid Leukemia Cells

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    Pettersson, Filippa; Retrouvey, Hélène; Skoulikas, Sophia; Miller, Wilson H.

    2011-01-01

    Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clinically relevant concentrations, vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Additionally, AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a reduction in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre-treatment with the antioxidant N-acetyl cysteine (NAC) reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents. PMID:21695163

  15. Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia.

    Science.gov (United States)

    Majeti, Ravindra

    2014-01-01

    Massively parallel DNA sequencing has uncovered recurrent mutations in many human cancers. In acute myeloid leukemia (AML), cancer genome/exome resequencing has identified numerous recurrently mutated genes with an average of 5 mutations in each case of de novo AML. In order for these multiple mutations to accumulate in a single lineage of cells, they are serially acquired in clones of self-renewing hematopoietic stem cells (HSC), termed pre-leukemic HSC. Isolation and characterization of pre-leukemic HSC have shown that their mutations are enriched in genes involved in regulating DNA methylation, chromatin modifications, and the cohesin complex. On the other hand, genes involved in regulating activated signaling are generally absent. Pre-leukemic HSC have been found to persist in clinical remission and may ultimately give rise to relapsed disease through the acquisition of novel mutations. Thus, pre-leukemic HSC may constitute a key cellular reservoir that must be eradicated for long-term cures. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Radotinib induces high cytotoxicity in c-KIT positive acute myeloid leukemia cells.

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    Heo, Sook-Kyoung; Noh, Eui-Kyu; Kim, Jeong Yi; Jo, Jae-Cheol; Choi, Yunsuk; Koh, SuJin; Baek, Jin Ho; Min, Young Joo; Kim, Hawk

    2017-06-05

    Previously, we reported that radotinib, a BCR-ABL1 tyrosine kinase inhibitor, induced cytotoxicity in acute myeloid leukemia (AML) cells. However, the effects of radotinib in the subpopulation of c-KIT-positive AML cells were unclear. We observed that low-concentration radotinib had more potent cytotoxicity in c-KIT-positive cells than c-KIT-negative cells from AML patients. To address this issue, cell lines with high c-KIT expression, HEL92.1.7, and moderate c-KIT expression, H209, were selected. HEL92.1.7 cells were grouped into intermediate and high c-KIT expression populations. The cytotoxicity of radotinib against the HEL92.1.7 cell population with intermediate c-KIT expression was not different from that of the population with high c-KIT expression. When H209 cells were grouped into c-KIT expression-negative and c-KIT expression-positive populations, radotinib induced cytotoxicity in the c-KIT-positive population, but not the c-KIT-negative population. Thus, radotinib induces cytotoxicity in c-KIT-positive cells, regardless of the c-KIT expression intensity. Therefore, radotinib induces significant cytotoxicity in c-KIT-positive AML cells, suggesting that radotinib is a potential target agent for the treatment of c-KIT-positive malignancies including AML. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults.

    Science.gov (United States)

    Babushok, Daria V; Bessler, Monica; Olson, Timothy S

    2016-01-01

    Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes.

  18. When should patients receive consolidation chemotherapy before allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission?

    Science.gov (United States)

    Yeshurun, Moshe; Wolach, Ofir

    2018-03-01

    Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative therapy for patients with acute myeloid leukemia. Despite the associated graft-versus-leukemia effect, leukemia relapse remains the most common cause of treatment failure after alloHCT. Here, we review the available data on whether there is an advantage in providing pretransplant consolidation chemotherapy prior to alloHCT. Randomized controlled studies are lacking. Data derive largely from four large retrospective registry studies. These analyses are consistent in demonstrating the lack of any survival benefit for pretransplant consolidation chemotherapy once a patient achieves a complete remission and a donor is readily available. These results are valid across conditioning regimen intensities, donor sources, and doses of cytarabine administered during consolidation. Available evidence suggests that patients with acute myeloid leukemia in first complete remission for whom a suitable donor is readily available should not be given pretransplant consolidation before proceeding to alloHCT, regardless of conditioning regimen intensity and that transplantation should be offered promptly at the time remission is achieved without undue delay. Nevertheless, patients for whom a suitable donor is not readily available after achieving first remission, should probably receive 'bridging' consolidation chemotherapy while waiting for a donor to be identified in an attempt to decrease the risk of early disease recurrence before transplantation. The role of minimal residual disease and genetic markers in directing consolidation choices are unclear to date.

  19. Induction chemotherapy versus palliative treatment for acute myeloid leukemia in a consecutive cohort of elderly patients.

    Science.gov (United States)

    Colovic, Milica; Colovic, Natasa; Radojkovic, Milica; Stanisavljevic, Dejana; Kraguljac, Nada; Jankovic, Gradimir; Tomin, Dragica; Suvajdzic, Nada; Vidovic, Ana; Atkinson, Henry Dushan

    2012-09-01

    A retrospective survey of 210 consecutive patients aged ≥ 65 years (median age 69 years, range 65-88 years) with acute myeloid leukemia (AML) diagnosed at a single center over a 6-year period (January 2001 to December 2006) is presented. De novo AML was diagnosed in 179 (85.2 %) patients and 31 (14.7 %) patients had a secondary AML. Twenty-three patients had M0 (11 %), 36 M1 (17.15 %), 57 M2 (27.1 %), eight M3 (3.8 %), 45 M4 (21.4 %), 31 M5 (14.8 %), one M6 (0.5 %), one M7 (0.5 %), and eight patients had unclassified myeloid leukemia (3.8 %) according to French-American-British (FAB) Study Group Classification. Eight patients with M3 (acute promyelocytic leukemia) were excluded from the study. Cytogenetic analysis was performed in 172/202 (85 %) patients. The normal karyotype was found in 81/172 (47 %), high risk aberrations in 32/172 (18.6 %), and favorable karyotype in 13/172 (7.5 %) patients. Supportive and palliative therapies were applied in 115 (56.9 %) patients, a no induction chemotherapy (NIC) group, and 87 (43.1 %) patients received induction chemotherapy (IC group). Complete remission (CR) was achieved in 45/87 (51.7 %) in the IC group and in 5/115 (4.3 %) in the NIC group of patients. After a median follow up of 4 years, 194 (96 %) patients died. The variables significantly associated with a longer overall survival (OS) by univariate analysis were an age of <75 years, a better ECOG performance status (PS) (p = 0.000, CI 95.0 %, 1.358-2.049), a serum LDH activity <600 U/l (p = 0.000, CI 95.0 %, 1.465-2.946), lower white blood cell (WBC) count at diagnosis (p = 0.011, CI 95.0 %, 1.102-2.100), lower comorbidity HCT-CI index (p = 0.000, CI 95 % 2.209-3.458), absence of splenomegaly (p = 0.015, CI 95.0 %, 1.082-2.102) and hepatomegaly (p = 0.008, CI 95.0 %, 1.125-2.171), and no preceding nonhematological malignancy. Multivariate analysis showed that significant factors affecting OS in the IC group were achievement of CR (p = 0.000), the ECOG PS (p = 0

  20. The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia.

    Science.gov (United States)

    Both, Anna; Krauter, Jürgen; Damm, Frederik; Thol, Felicitas; Göhring, Gudrun; Heuser, Michael; Ottmann, Oliver; Lübbert, Michael; Wattad, Mohammed; Kanz, Lothar; Schlimok, Günter; Raghavachar, Aruna; Fiedler, Walter; Kirchner, Hartmut; Brugger, Wolfram; Schlegelberger, Brigitte; Heil, Gerhard; Ganser, Arnold; Wagner, Katharina

    2017-06-01

    Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.

  1. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study.

    Science.gov (United States)

    Metzeler, Klaus H; Maharry, Kati; Radmacher, Michael D; Mrózek, Krzysztof; Margeson, Dean; Becker, Heiko; Curfman, John; Holland, Kelsi B; Schwind, Sebastian; Whitman, Susan P; Wu, Yue-Zhong; Blum, William; Powell, Bayard L; Carter, Thomas H; Wetzler, Meir; Moore, Joseph O; Kolitz, Jonathan E; Baer, Maria R; Carroll, Andrew J; Larson, Richard A; Caligiuri, Michael A; Marcucci, Guido; Bloomfield, Clara D

    2011-04-01

    To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML). Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays. TET2 mutations, found in 23% of patients, were associated with older age (P classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.

  2. Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia.

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    Carolyn Glass

    Full Text Available The ecotropic virus integration site 1 (EVI1 transcription factor is associated with human myeloid malignancy of poor prognosis and is overexpressed in 8-10% of adult AML and strikingly up to 27% of pediatric MLL-rearranged leukemias. For the first time, we report comprehensive genomewide EVI1 binding and whole transcriptome gene deregulation in leukemic cells using a combination of ChIP-Seq and RNA-Seq expression profiling. We found disruption of terminal myeloid differentiation and cell cycle regulation to be prominent in EVI-induced leukemogenesis. Specifically, we identified EVI1 directly binds to and downregulates the master myeloid differentiation gene Cebpe and several of its downstream gene targets critical for terminal myeloid differentiation. We also found EVI1 binds to and downregulates Serpinb2 as well as numerous genes involved in the Jak-Stat signaling pathway. Finally, we identified decreased expression of several ATP-dependent P2X purinoreceptors genes involved in apoptosis mechanisms. These findings provide a foundation for future study of potential therapeutic gene targets for EVI1-induced leukemia.

  3. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia

    Science.gov (United States)

    Zhang, Mei-Jie; Bacigalupo, Andrea A.; Bashey, Asad; Appelbaum, Frederick R.; Aljitawi, Omar S.; Armand, Philippe; Antin, Joseph H.; Chen, Junfang; Devine, Steven M.; Fowler, Daniel H.; Luznik, Leo; Nakamura, Ryotaro; O’Donnell, Paul V.; Perales, Miguel-Angel; Pingali, Sai Ravi; Porter, David L.; Riches, Marcie R.; Ringdén, Olle T. H.; Rocha, Vanderson; Vij, Ravi; Weisdorf, Daniel J.; Champlin, Richard E.; Horowitz, Mary M.; Fuchs, Ephraim J.; Eapen, Mary

    2015-01-01

    We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation. PMID:26130705

  4. Hypothyroidism following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.

    Science.gov (United States)

    Medinger, Michael; Zeiter, Deborah; Heim, Dominik; Halter, Jörg; Gerull, Sabine; Tichelli, André; Passweg, Jakob; Nigro, Nicole

    2017-07-01

    Hypothyroidism may complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT); we therefore analyzed risk factors in this study. We studied 229 patients with acute myeloid leukemia (AML) who underwent an allo-HSCT between 2003 and 2013 with different conditioning regimens (myeloablative, reduced-intensity, chemotherapy-based, or total body irradiation-based). Thyroid-stimulating hormone (TSH) and free thyroxine levels (fT4) were available in 104 patients before and after allo-HSCT. The median age at transplantation (n=104) was 47 (IQR 40-59)], 37 (35.6%) patients were female, and the overall mortality was 34.6% (n=36). After a median follow-up period of 47 (IQR 25-84) months, overt hypothyroidism (basal TSH>4.49mIU/l, FT4hypothyroidism (basal TSH>4.49mIU/l, normal fT4) was observed in 20 patients (19.2%). Positive thyroperoxidase (TPO) antibodies were found in 5 (4.8%) patients. A total of 13 patients (12.5%) were treated with thyroid hormone replacement. Acute graft-versus-host disease (aGvHD) ≥grade 2 occurred in 55 (52.9%) and chronic GvHD (cGvHD) in 74 (71.2%) of the patients. The risk of developing hypothyroidism was higher in the patients with repeated allo-HSCTs (P=0.024) and with positive TPO antibodies (P=0.045). Furthermore, the development of overt hypothyroidism was inversely proportional to age (P=0.043). No correlation was found with GvHD, HLA-mismatch, total body irradiation, and gender. After allo-HSCT, a significant number of patients experience thyroid dysfunction, including subclinical and overt hypothyroidism. Long-term and continuous follow-up for thyroid function after HSCT is important to provide timely and appropriate treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. KRAS (G12D Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia

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    Shanmin Zhao

    2014-01-01

    Full Text Available Background/Aims: It has been demonstrated that KRAS mutations represent about 90% of cancer-associated mutations, and that KRAS mutations play an essential role in neoplastic transformation. Cancer-associated RAS mutations occur frequently in acute myeloid leukemia (AML, suggesting a functional role for Ras in leukemogenesis. Methods: We successfully established a mouse model of human leukemia by transplanting bone marrow cells co-transfected with the K-ras (G12D mutation and AML1/ETO fusion protein. Results: Mice transplanted with AML/ETO+KRAS co-transduced cells had the highest mortality rate than mice transplanted with AML/ETO- or KRAS-transduced cells (115d vs. 150d. Upon reaching a terminal disease stage, EGFP-positive cells dominated their spleen, lymph nodes, peripheral blood and central nervous system tissue. Immunophenotyping, cytologic analyses revealed that AML/ETO+KRAS leukemias predominantly contained immature myeloid precursors (EGFP+/c-Kit+/Mac-1-/Gr-1-. Histologic analyses revealed that massive leukemic infiltrations were closely packed in dense sheets that effaced the normal architecture of spleen and thymus in mice transplanted with AML1/ETO + KRAS co-transduced cells. K-ras mRNA and protein expression were upregulated in bone marrow cells of the K-ras group and AML1/ETO + Kras group. The phosphorylation of MEK/ERK was significantly enhanced in the AML1/ETO + Kras group. The similar results of the AML1/ETO + Nras group were consistent with those reported previously. Conclusion: Co-transduction of KrasG12D and AML1/ETO induces acute monoblastic leukemia. Since expression of mutant K-ras alone was insufficient to induce leukemia, this model may be useful for investigating the multi-step leukemogenesis model of human leukemia.

  6. Acute myeloid leukemia is a disease associated with HLA-C3.

    Science.gov (United States)

    Yoon, Jeongsook

    2015-01-01

    We aimed to observe human leukocyte antigen (HLA) associations with human acute myeloid leukemia (AML) in a large population, in order to investigate the roles of HLA in leukemogenesis. Furthermore, we examined the HLA association according to morphological, cytogenetic, immunological, and clinical classifications. We performed HLA genotyping, bone marrow studies, cytogenetic analyses, and fluorescence-activated cell sorting analyses. A clinical outcome database was constructed, and the HLA frequency, gene frequency, relative risk (RR), linkage disequilibrium, and the 2-locus and 3-locus haplotype frequency using the Mattiuz formula were calculated. For the healthy controls, Korean HLA data published by Park and co-workers were used. AML was found to be associated with HLA-C3 (RR = 1.46; p classification, acute myelomonocytic leukemia (AML-M4) was associated with HLA-C3 (47.2 vs. 74.1%; RR = 3.13; p = 0.005), in cytogenetic classification, del(9), which is frequently observed in AML-M4, was also associated with HLA-C3 (47.2 vs. 100%; RR = 13.43; p = 0.024), and in clinical classification, incomplete remission was associated with HLA-C3 as well (47.2 vs. 63.2%; RR = 1.92; p = 0.002). No correlations between AML and immunological classifications were observed. Moreover, and in terms of 2-locus haplotypes, AML was found to be associated with HLA-C3/B62 (HLA-C3 gene frequency 0.3415; HLA-B62 gene frequency 0.1361; linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 6.0%; p classification, incomplete remission (linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 13.6%; p = 0.013) and relapse (linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 71.0%; p = 0.044) were associated with HLA-C3/B62, whereas no association was observed for FAB, cytogenetic and immunological classifications. No association was observed for the 3-locus haplotype. The HLA-C3 antigen and the 2-locus haplotype are associated with AML. © 2014 S. Karger AG, Basel.

  7. Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia.

    Science.gov (United States)

    Chisini, Marta; Stefanizzi, Caterina; Ceglie, Teresa; Raponi, Sara; Vozella, Federico; Colafigli, Gioia; Salaroli, Adriano; D'Angiò, Mariella; Mancini, Marco; Diverio, Daniela; Breccia, Massimo; Mancini, Francesca; Minotti, Clara; Trisolini, Silvia; Capria, Saveria; Testi, Anna Maria; Guarini, Anna; Latagliata, Roberto; De Propris, Maria Stefania; Foà, Robin

    2017-12-01

    The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9-81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6-176.0), with 2-year disease-free survival rate of 45.1% (95% confidence interval 39.6-50.6). The median overall survival was 14.4 months (range 0.3-177.0), with 2-year overall survival rate of 42.2% (95% confidence interval 37.5-46.9). At univariate analysis for CR achievement, age classification (P = .045), low-risk karyotype (P  8 g/dL (P = .020), and white blood cell < 50 × 10 9 /L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 10 9 /L (P = .017), and low-risk/no high-risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement. The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

    KAUST Repository

    Madhoun, Nour Y.

    2017-04-01

    Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. Here, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes during differentiation induction of AML cells using anti-CD44 mAbs and other two previously reported differentiation agents. In the first objective (Chapter 4), our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. In the second objective (Chapter 5), 1H NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a

  9. Acute Panmyelosis with Myelofibrosis - A Rare Subtype of Acute Myeloid Leukemia

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    Tathagata Chatterjee

    2013-06-01

    Full Text Available One case of acute panmyelosis with myelofibrosis (APMF is being reported. A 45 year old male presented with abrupt onset of rapidly progressing low backache, weakness and pancytopenia. On examination there was no organomegaly. Peripheral blood examination revealed normocytic normochromic red blood cells with 10% circulating blasts. Flowcytometric examination of peripheral blood revealed blasts which were positive for CD 34 ,HLA- DR and myeloid associated antigens (i.e. CD13 and CD33.Blasts were negative for anti MPO. Bone marrow aspirate resulted in a dry tap. Bone marrow biopsy revealed panmyeloid proliferation with scattered blasts which were CD 34 positive on imunohistochemistry and negative for anti MPO. Reticulin stain showed grade III myelofibrosis (WHO. Differential diagnosis considered included AML-M7, MDS-RAEB II and AML with myelodysplasia . He was started on chemotherapy [idarubicin and cytarabine; 3+7 induction regimen followed by three cycles of HIDAC (High dose cytosine arabinoside] after which patient was in complete morphological remission with markedly reduced bone marrow fibrosis. He is now being worked up for allogeneic stem cell transplantation. Patient is asymptomatic at eight months of diagnosis. In conclusion these patients should be managed aggressively with AML therapy and this case report reaffirms the fact that APMF is subtype of AML.

  10. Investigating the microRNA-mRNA regulatory network in acute myeloid leukemia.

    Science.gov (United States)

    Zhang, Haiguo; Zhang, Chengfang; Feng, Rui; Zhang, Haixia; Gao, Min; Ye, Ling

    2017-10-01

    Acute myeloid leukemia (AML) is a common myelogenous malignancy in adults that is often characterized by disease relapse. The pathophysiological mechanism of AML has not yet been elucidated. The present study aimed to identify the crucial microRNAs (miRNAs/miRs) and target genes in AML, and to uncover the potential oncogenic mechanism of AML. miRNA and mRNA expression-profiling microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed and a regulatory network between miRNAs and target genes was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to predict the biological functions of the differentially expressed genes. Reverse transcription-quantitative polymerase chain reaction analysis was employed to verify the expression levels of miRNAs and target genes in AML patient samples. A total of 86 differentially expressed miRNAs and 468 differentially expressed mRNAs between AML and healthy blood samples were identified. In total, 47 miRNAs and 401 mRNAs were found to be upregulated, and 39 miRNAs and 67 mRNAs were found to be downregulated in AML. A total of 223 miRNA-target genes pairs were subjected to the construction of a regulatory network. Differentially expressed target genes were significantly enriched in the Wnt signaling pathway (hsa04310), melanogenesis (hsa04916) and pathways in cancer (hsa05200). Significantly differentially expressed miRNAs and genes, including hsa-miR-155, hsa-miR-192, annexin A2 ( ANXA2 ), frizzled class receptor 3 ( FZD3 ), and pleomorphic adenoma gene 1 ( PLAG1 ), may serve essential roles in AML oncogenesis. Overall, hsa-miR-155, hsa-miR-192, ANXA2 , FZD3 and PLAG1 may be associated with the development of AML via the involvement of the Wnt signaling pathway, melanogenesis and other cancer-associated signaling pathways.

  11. Phase I-II study of aclacinomycin for a treatment of acute myeloid leukemia.

    Science.gov (United States)

    Machover, D; Gastiaburu, J; Delgado, M; Goldschmidt, E; Hulhoven, R; Misset, J L; de Vassal, F; Tapiero, H; Dorval, T; Ribaud, P

    1984-01-01

    Aclacinomycin A (ACM) was administered for induction treatment to 40 previously treated acute myeloid leukemia (AML) patients. 38 patients aged 2 to 80 years (mean +/- SE, 35.0 +/- 3.2 years) with overt AML were evaluated; of these, seventeen patients were given ACM after an unsuccessful attempt to obtain a complete remission (CR) with various regimens comprising adriamycin (ADM) or daunorubicin (DNR) and were considered resistant to these drugs. Thirteen patients received ACM at a daily dose of 10 to 30 mg/m2 IV bolus until the maximum total dose of 300 mg/m2 per course was reached or until unacceptable toxicity appeared; of these patients, 2 (15%) attained a CR. Twenty-five patients were given 10-day courses of ACM at the daily dose of 15 mg/m2 IV bolus with 10-day intervals between courses; with this regimen 11 patients (44%) attained a CR. The overall CR rate was 34%. Total doses necessary to attain a CR ranged from 150 to 600 mg/m2. CR was attained by 6 patients (35%) of the 17 who were previously resistant to ADM or DNR. The incidence and severity of the toxic effects such as mucositis, diarrhea, vomiting and infection were related to the dose of ACM administered during each course of therapy. However, in patients who received 150 mg/m2 per course the toxicity was within acceptable limits. Alopecia was not observed. Transient T-wave inversion was observed in 3 patients and atrial flutter developed in one patient. Therefore, we conclude that ACM is a new major drug in the treatment of AML.

  12. Epigenetic targeting in acute myeloid leukemia: use of flow cytometry in monitoring therapeutic effects.

    Science.gov (United States)

    Ryningen, Anita; Bruserud, Øystein

    2007-12-01

    Flow cytometric techniques have emerged as a powerful tool in hematology allowing fast, sensitive and reproducible multi-parametric analyses at the single cell level of heterogeneous samples. Small subsets of cells can be studied with high degree of accuracy, and a broad and constantly increasing specter of antibodies is available. Flow cytometry has therefore become the method of choice for evaluation of therapeutic effects at single cell level. These methodological approaches can easily be used to study hematological malignancies, and the future use of this strategy in other malignancies will depend on the development of laboratory techniques to prepare suspensions of viable cells also from tumor biopsies. The selection of biological parameters for evaluation of treatment effects should probably be based on (i) molecular markers involved in cancer-associated genetic abnormalities; (ii) other molecular markers showing altered expression in the malignant cells and thought to be involved in leukemogenesis or having a prognostic impact; (ii) functional assays known to reflect biological characteristics that are important in carcinogenesis (e.g. cell cycle distribution, functional evaluation of apoptosis regulation). These molecules will in addition often represent the therapeutic targets when new anticancer drugs are developed. In this review we use treatment of acute myeloid leukemia with histone deacetylase inhibitors as an example. Based on the criteria mentioned above we suggest that the monitoring of therapeutic effects on the cancer cells in these patients should include differentiation status, histone acetylation, cell cycle distribution, pro- and anti-apoptotic signaling balance and intracellular levels of various transcription factors.

  13. [Cytogentic and prognostic characteristic of acute myeloid leukemia with monosomal karyotype].

    Science.gov (United States)

    Li, Z; Wei, H; Lin, D; Zhou, C L; Liu, B C; Wang, Y; Liu, K Q; Li, W; Gong, B F; Wei, S N; Zhang, G J; Zhao, X L; Li, Y; Liu, Y T; Gong, X Y; Gu, R X; Qiu, S W; Mi, Y C; Wang, J X

    2016-05-14

    To explore the cytogenetic and prognostic significance of monosomal karyotype (MK) in adult patients with acute myeloid leukemia (AML). From September 2002 to November 2014 in Blood Diseases Hospital, Chinese Academy of Medical Sciences, 97 cases with AML were enrolled, including 96 cases within unfavorable cytogenetic category and an MK case within the intermediate category. The clinical data of MK-positive cases and unfavorable risk MK-negative cases were analyzed. There were 31 MK cases, accounting for 2.5% of the AML patients treated at the same period. Thirty of them were complex aberrant karyotypes defined as showing three or more clonal abnormalities and classified into adverse group based on SWOG criteria. The rest one of these 31 MK was intermediate risk according to SWOG criteria. Among MK cases, the most frequent monosomal chromosome were -17, -5, -7, -21, -8, -22. In 96 cytogenetic unfavorable AML cases, the median OS period was 6.1 months for MK, the median OS period did not reach for non-MK AML (P=0.001). And the median relapse free survival (RFS) period was 3.1 and 18.6 months for MK and non-MK AML (Pkaryotype AML cases, the median OS was 6.1 and 10.8 months for MK and non-MK AML (P=0.088), respectively. And the median RFS was 3.1 and 8.6 months for MK and non-MK AML (P=0.009), respectively. The RFS varied significantly between MK and non-MK categories. Most MK patients were complex karyotype in cytogenetic unfavorable group. Within unfavorable or complex karyotype categories, MK-positive cases had a more adverse prognosis than MK-negative cases.

  14. Improved survival outcome of childhood acute myeloid leukemia with intensified chemotherapy in Chinese children.

    Science.gov (United States)

    Zhai, Xiao Wen; Cheng, Frankie Wai Tsoi; Lee, Vincent; Leung, Wing Kwan; Ng, Margaret Heung Ling; Tsang, Kam Sze; Shing, Ming Kong; Li, Chi Kong

    2011-05-01

    With the use of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT), the prognosis of childhood acute myeloid leukemia (AML) improved over the last 2 decades. Survival data of Chinese pediatric patients were seldom reported. The authors adopted modified UK Medical Research Council (MRC) AML protocols for treatment of childhood AML since 1994. From 1994 to 2008, the outcomes of Chinese AML patients were studied. Sixty-eight patients were studied. The median age at diagnosis was 9.9 years. Twenty-five patients (36.8%) had favorable cytogenetic karyotypes, including t(15;17), t(8;21) and inv(16). Complete remission (CR) rate was 91.2%. The relapse rate was 29.4%. For non-M3 patients, the 5-year overall survival (pOS) was 64% ± 7% and event-free survival (pEFS) was 53% ± 7%. For those non-good-risk patients who achieved CR, there were no significant differences in outcomes between patients who received HSCT in CR1 and those received chemotherapy alone (5-year pOS 80% ± 13% and 69% ± 9%, P = .52), 5-year pEFS 69% ± 15% and 55% ± 10%, P = .40). The pOS of the 20 relapsed patients was 29% ± 11%. Sixteen patients with t(8;21) and inv(16) had similar outcome with those without favorable cytogenetics (pOS 66% ± 12% versus 65% ± 7%, P = .39; pEFS 60% ± 11% versus 54% ± 8%, P = .45). Patients who achieved CR after 2 or more courses of chemotherapy and presenting white blood cell count (WBC) ≥ 100 × 10(9)/L had poorer outcome (pOS 40% versus 80%P < .01; 43% versus 70%, P = .02, respectively). Intensified chemotherapy improved outcome of Chinese AML children. CR after first course of chemotherapy and WBC at diagnosis were important prognostic factors.

  15. Classification of pediatric acute myeloid leukemia based on miRNA expression profiles.

    Science.gov (United States)

    Obulkasim, Askar; Katsman-Kuipers, Jenny E; Verboon, Lonneke; Sanders, Mathijs; Touw, Ivo; Jongen-Lavrencic, Mojca; Pieters, Rob; Klusmann, Jan-Henning; Michel Zwaan, C; van den Heuvel-Eibrink, Marry M; Fornerod, Maarten

    2017-05-16

    Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with respect to biology as well as outcome. In this study, we investigated whether known biological subgroups of pediatric AML are reflected by a common microRNA (miRNA) expression pattern. We assayed 665 miRNAs on 165 pediatric AML samples. First, unsupervised clustering was performed to identify patient clusters with common miRNA expression profiles. Our analysis unraveled 14 clusters, seven of which had a known (cyto-)genetic denominator. Finally, a robust classifier was constructed to discriminate six molecular aberration groups: 11q23-rearrangements, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17) (q21;q22), NPM1 and CEBPA mutations. The classifier achieved accuracies of 89%, 95%, 95%, 98%, 91% and 96%, respectively. Although lower sensitivities were obtained for the NPM1 and CEBPA (32% and 66%), relatively high sensitivities (84%-94%) were attained for the rest. Specificity was high in all groups (87%-100%). Due to a robust double-loop cross validation procedure employed, the classifier only employed 47 miRNAs to achieve the aforementioned accuracies. To validate the 47 miRNA signatures, we applied them to a publicly available adult AML dataset. Albeit partial overlap of the array platforms and molecular differences between pediatric and adult AML, the signatures performed reasonably well. This corroborates our claim that the identified miRNA signatures are not dominated by sample size bias in the pediatric AML dataset. In conclusion, cytogenetic subtypes of pediatric AML have distinct miRNA expression patterns. Reproducibility of the miRNA signatures in adult dataset suggests that the respective aberrations have a similar biology both in pediatric and adult AML.

  16. Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia

    Science.gov (United States)

    Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T.; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R.; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D.; Lutz, Christoph

    2017-01-01

    In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. PMID:28550184

  17. Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia.

    Science.gov (United States)

    Mansour, Iman; Zayed, Rania A; Said, Fadwa; Latif, Lamyaa Abdel

    2016-09-01

    The microenvironment of acute myeloid leukemia (AML) is suppressive for immune cells. Regulatory T cells (Tregs) have been recognized to play a role in helping leukemic cells to evade immunesurveillance. The mesenchymal stem cells (MSCs) are essential contributors in immunomodulation of the microenvironment as they can promote differentiation of Tregs via the indoleamine 2,3-dioxygenase (IDO) pathway. The aim of the present work was to evaluate the expression of IDO in bone marrow derived MSCs and to study its correlation to percentage of Tregs. Thirty-seven adult bone marrow samples were cultured in appropriate culture medium to isolate MSCs. Successful harvest of MSCs was determined by plastic adherence, morphology, and positive expression of CD271 and CD105; negative expression of CD34 and CD45 using flowcytometry. MSCs were examined for IDO expression by immunocytochemistry using anti-IDO monoclonal antibody. CD4+ CD25+ cells (Tregs) were measured in bone marrow samples by flowcytometry. MSCs were successfully isolated from 20 of the 37 bone marrow samples cultured. MSCs showed higher expression of IDO and Tregs percentage was higher in AML patients compared to control subjects (P = 0.002 and P < 0.001, respectively). A positive correlation was found between IDO expression and Tregs percentage (P value = 0.012, r = 0.5). In this study, we revealed an association between high IDO expression in MSCs and elevated levels of Tregs which could have an important role in the pathogenesis of AML, providing immunosuppressive microenvironment.

  18. Geographic Heterogeneity of the AML1-ETO Fusion Gene in Iranian Patients with Acute Myeloid Leukemia

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    Saeedeh Ghazaey Zidanloo

    2014-10-01

    Full Text Available Background: The human AML1 gene, located on chromosome 21, can be fused to the AML1- eight-twenty-one (ETO oncoprotein on chromosome eight, resulting in a t(8;21(q22;q22 translocation. Acute myeloid leukemia (AML associated with this translocation is considered a distinct AML with a favorable prognosis. Due to the various incidences of the translocation, which is associated with geographic diversities, investigation of molecular epidemiology is important to increase the awareness of physicians and hematologists regarding the frequency this chromosomal aberration. Methods: The patients were classified according to the French–American–British classification into eight groups: M0–M7. Determination of the prevalence of the AML1-ETO fusion gene was accomplished by TaqMan real-time PCR. Bone marrow samples from 113 patients with newly-diagnosed, untreated AML -M1, -M2, and -M4, and 20 healthy controls admitted to the Ghaem Hospital in Mashhad, Iran were studied. Results: The AML1-ETO fusion gene was detected up 50% of the M2 subgroup and absent in the M1 and M4 subtypes and healthy controls. Comparison of the prevalence of the t(8;21 translocation with results of previous studies showed that it varies between countries. This result may be due to geographic or ethnic differences, or both. Conclusions: The relatively high prevalence of the t(8;21 translocation in Iran was similar to that found in other Asian countries. It was closely associated with female gender, relatively young age, and FAB-M2 subtype. Its distribution varied considerably with geographic area. Therefore, further studies are needed to provide epidemiological data important for the establishment of optimal therapeutic strategies applicable to patients of each region.

  19. DNMT3A GENE POINT MUTATIONS DETECTION IN ACUTE MYELOID LEUKEMIA PATIENTS USING SEQUENCING TECHNIQUE

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    A. V. Vinogradov

    2015-01-01

    Full Text Available Aim: to estimate the frequency of DNMT3A gene exons 18–26 point mutations in acute myeloid leukemia (AML patients (pts using target automatic sequencing technique.Material and Methods. Bone marrow and peripheral blood samples were obtained from 34 AML pts aged 21 to 64, who were treated in Sverdlovsk Regional Hematological Centre (Ekaterinburg during the period 2012–2014. Distribution of the pts according to FAB-classification was as follows: AML M0 – 3, M1 – 1, M2 – 12, M3 – 3, M4 – 10, M5 – 2, M6 – 1, M7 – 1, blastic plasmacytoid dendritic cell neoplasm – 1. Total RNA was extracted from leukemic cells and subjected to reverse transcription. DNMT3A gene exons 18–26 were amplified by PCR. Detection of mutations in DNMT3A gene was performed by direct sequencing. Sequencing was realized using an automatic genetic analyzer ABI Prism 310.Results. The average frequency of functionally significant point mutations in DNMT3A gene exons 18– 26 among the treated AML pts was 5.9%. They were detected in morphological subgroups M2 and M4(according to WHO classification. The average frequency of DNMT3A gene exons 18–26 point mutations among the AML M2 and M4 pts without chromosomal aberrations and TP53 gene point mutations was 14.3%. In both cases there were samples in which DNMT3A gene mutations were accompanied by molecular lesions of NPM1, KRAS and WT1 genes. AML pts with DNMT3A gene exons 18–26 point mutations characterized by poor response to standard chemotherapeutic regimens and unfavorable prognosis.

  20. Identification of Gene Networks Associated with Acute Myeloid Leukemia by Comparative Molecular Methylation and Expression Profiling

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    Margaret Dellett

    2010-01-01

    Full Text Available Around 80% of acute myeloid leukemia (AML patients achieve a complete remission, however many will relapse and ultimately die of their disease. The association between karyotype and prognosis has been studied extensively and identified patient cohorts as having favourable [e.g. t(8; 21, inv (16/t(16; 16, t(15; 17], intermediate [e.g. cytogenetically normal (NK-AML] or adverse risk [e.g. complex karyotypes]. Previous studies have shown that gene expression profiling signatures can classify the sub-types of AML, although few reports have shown a similar feature by using methylation markers. The global methylation patterns in 19 diagnostic AML samples were investigated using the Methylated CpG Island Amplification Microarray (MCAM method and CpG island microarrays containing 12,000 CpG sites. The first analysis, comparing favourable and intermediate cytogenetic risk groups, revealed significantly differentially methylated CpG sites (594 CpG islands between the two subgroups. Mutations in the NPM1 gene occur at a high frequency (40% within the NK-AML subgroup and are associated with a more favourable prognosis in these patients. A second analysis comparing the NPM1 mutant and wild-type research study subjects again identified distinct methylation profiles between these two subgroups. Network and pathway analysis revealed possible molecular mechanisms associated with the different risk and/or mutation sub-groups. This may result in a better classification of the risk groups, improved monitoring targets, or the identification of novel molecular therapies.

  1. Feature genes predicting the FLT3/ITD mutation in acute myeloid leukemia.

    Science.gov (United States)

    Li, Chenglong; Zhu, Biao; Chen, Jiao; Huang, Xiaobing

    2016-07-01

    In the present study, gene expression profiles of acute myeloid leukemia (AML) samples were analyzed to identify feature genes with the capacity to predict the mutation status of FLT3/ITD. Two machine learning models, namely the support vector machine (SVM) and random forest (RF) methods, were used for classification. Four datasets were downloaded from the European Bioinformatics Institute, two of which (containing 371 samples, including 281 FLT3/ITD mutation-negative and 90 mutation‑positive samples) were randomly defined as the training group, while the other two datasets (containing 488 samples, including 350 FLT3/ITD mutation-negative and 138 mutation-positive samples) were defined as the test group. Differentially expressed genes (DEGs) were identified by significance analysis of the microarray data by using the training samples. The classification efficiency of the SCM and RF methods was evaluated using the following parameters: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the area under the receiver operating characteristic curve. Functional enrichment analysis was performed for the feature genes with DAVID. A total of 585 DEGs were identified in the training group, of which 580 were upregulated and five were downregulated. The classification accuracy rates of the two methods for the training group, the test group and the combined group using the 585 feature genes were >90%. For the SVM and RF methods, the rates of correct determination, specificity and PPV were >90%, while the sensitivity and NPV were >80%. The SVM method produced a slightly better classification effect than the RF method. A total of 13 biological pathways were overrepresented by the feature genes, mainly involving energy metabolism, chromatin organization and translation. The feature genes identified in the present study may be used to predict the mutation status of FLT3/ITD in patients with AML.

  2. HAG regimen improves survival in adult patients with hypocellular acute myeloid leukemia.

    Science.gov (United States)

    Hu, Xiaoxia; Fu, Weijun; Wang, Libing; Gao, Lei; Lü, Shuqin; Xi, Hao; Qiu, Huiying; Chen, Li; Chen, Jie; Ni, Xiong; Xu, Xiaoqian; Zhang, Weiping; Yang, Jianmin; Wang, Jianmin; Song, Xianmin

    2016-01-19

    Hypocellular acute myeloid leukemia (Hypo-AML) is a rare disease entity. Studies investigating the biological characteristics of hypo-AML have been largely lacking. We examined the clinical and biological characteristics, as well as treatment outcomes of hypo-AML in our institutes over a seven years period. We retrospectively analyzed data on 631 adult AML patients diagnosed according to the French-American-British (FAB) classification and WHO classification of tumors of haematopoietic and lymphoid tissue, including 43 patients with hypo-AML. Biological variables, treatment outcomes and follow-up data on hypo-AML patients were analyzed. Out of 631 AML patients, 47 (7.4%) were diagnosed as hypo-AML, out of which 43 patients were evaluable. Compared with non-hypocellular AML, hypo-AML patients tended to be older (P = 0.05), more likely to present with leukocytopenia (P < 0.01) and anterior hematological diseases (P = 0.02). The overall complete remission (CR) rate, disease free survival (DFS), and overall survival (OS) in hypo-AML patients were comparable to those in non-hypo AML patients. Twenty-seven (62.8%) patients with hypocellular AML were treated with the standard regimen of anthracyclines and cytarabine (XA) (associated CR rate: 51.9%; median OS: 7 months; median DFS: 6.5 months). Sixteen (37.2%) patients were treated with a priming regimen containing homoharringtonine, cytarabine and G-CSF (HAG) (associated CR rate: 81.25%; median OS: 16 months; median DFS: 16 months). The overall prognosis of hypo-AML was not inferior to that of non-hypo AML. HAG regimen might increase response rates and improve survival in hypo-AML patients.

  3. Health care utilization and end-of-life care for older patients with acute myeloid leukemia.

    Science.gov (United States)

    El-Jawahri, Areej R; Abel, Gregory A; Steensma, David P; LeBlanc, Thomas W; Fathi, Amir T; Graubert, Timothy A; DeAngelo, Daniel J; Wadleigh, Martha; Ballen, Karen K; Foster, Julia E; Attar, Eyal C; Amrein, Philip C; Brunner, Andrew M; Stone, Richard M; Temel, Jennifer S

    2015-08-15

    Health care utilization in older adults (age ≥60 years) with acute myeloid leukemia (AML) has not been well studied. We conducted a retrospective analysis of 330 consecutive older patients who were diagnosed with AML between May 1, 2005 and December 23, 2011, at 2 hospitals in Boston to examine their health care utilization and end-of-life care. Using multivariable logistic and linear regression models adjusting for covariates, we also compared health care utilization between patients who received intensive induction chemotherapy (n = 197; cytarabine/ anthracycline combination) versus nonintensive chemotherapy (n = 133; single-agent therapy). The median number of hospitalizations for the entire cohort was 4.2 (range, 1-18 hospitalizations). Patients who died spent a mean of 28.3% of their life after diagnosis in the hospital and 13.8% of their life attending outpatient clinic appointments. Although the majority of patients (87.9%) died during the 2-year follow-up period, a minority received palliative care (16.2%) or hospice (23.1%) services. Within 30 days of death, 84.5% of patients were hospitalized, and 61% died in the hospital. Among the patients who died, those who received intensive induction therapy (vs nonintensive therapy) spent 30% more of their life after diagnosis in the hospital (P < .0001) and were less likely to receive hospice services (odds ratio, 0.45; P = .05). The current findings highlight the intensity of health care utilization among older patients with AML, regardless of treatment modality. Despite the poor prognosis, palliative care and hospice services are rarely used. Future work should study novel health care delivery models to optimize care throughout the course of illness and at the end of life. © 2015 American Cancer Society.

  4. microRNAs and Acute Myeloid Leukemia Chemoresistance: A Mechanistic Overview

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    Martino Marco Gabra

    2017-10-01

    Full Text Available Up until the early 2000s, a functional role for microRNAs (miRNAs was yet to be elucidated. With the advent of increasingly high-throughput and precise RNA-sequencing techniques within the last two decades, it has become well established that miRNAs can regulate almost all cellular processes through their ability to post-transcriptionally regulate a majority of protein-coding genes and countless other non-coding genes. In cancer, miRNAs have been demonstrated to play critical roles by modifying or controlling all major hallmarks including cell division, self-renewal, invasion, and DNA damage among others. Before the introduction of anthracyclines and cytarabine in the 1960s, acute myeloid leukemia (AML was considered a fatal disease. In decades since, prognosis has improved substantially; however, long-term survival with AML remains poor. Resistance to chemotherapy, whether it is present at diagnosis or induced during treatment is a major therapeutic challenge in the treatment of this disease. Certain mechanisms such as DNA damage response and drug targeting, cell cycling, cell death, and drug trafficking pathways have been shown to be further dysregulated in treatment resistant cancers. miRNAs playing key roles in the emergence of these drug resistance phenotypes have recently emerged and replacement or inhibition of these miRNAs may be a viable treatment option. Herein, we describe the roles miRNAs can play in drug resistant AML and we describe miRNA-transcript interactions found within other cancer states which may be present within drug resistant AML. We describe the mechanisms of action of these miRNAs and how they can contribute to a poor overall survival and outcome as well. With the precision of miRNA mimic- or antagomir-based therapies, miRNAs provide an avenue for exquisite targeting in the therapy of drug resistant cancers.

  5. Metronomic therapy with oral 6-mercaptopurine in elderly acute myeloid leukemia: A prospective pilot study

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    Akhil Kapoor

    2016-01-01

    Full Text Available Introduction: Acute myeloid leukemia (AML in elderly patients differs biologically from that in younger patients and is known to have unfavorable chromosomal rearrangements, higher resistance, and lower tolerance to chemotherapy. In such circumstances, instead of giving full-blown chemotherapy, palliative metronomic chemotherapy (MCT could be a treatment option. Patients and Methods: We performed a prospective pilot study of old AML patients (age >60 years not amenable to curative treatment. Thirty-two patients were enrolled into the study and were treated with daily oral 6-mercaptopurine 75 mg/m 2 . The following inclusion criteria were used: age >60 years, nonpromyelocytic AML, the absence of uncontrolled comorbidities, and patient not amenable to curative treatment. Overall survival (OS was calculated using Kaplan-Meier method and Cox regression analysis were used to calculate the hazards ratio of significant factors. Results: The median age of the patients was 69 years (range: 61-86 years with male: female ratio of 2.5:1. About 59.4% of patients had Eastern Cooperative Oncology Group performance status of 2 while rest had the status of 3. The median OS was 6 months (95% confidence interval [CI]: 4.4-7.6. Males had median OS of 7 months (95% CI: 5.4-8.6 versus females with OS of 3 months (95% CI: 1.5-4.4; P = 0.008. There was no survival difference on the basis of baseline hemoglobin or French-American-British class. There were no Grade 4 toxicities and no episode of febrile neutropenia. Conclusions: MCT with oral 6-mercaptopurine is an attractive treatment option in elderly AML patients who are not amenable to curative therapy with minimal toxicities.

  6. Improved outcome in childhood acute myeloid leukemia in Singapore with the MRC AML 10 protocol.

    Science.gov (United States)

    Tan, Ronald M; Quah, Thuan Chong; Aung, Lele; Liang, Shen; Kirk, Richard C; Yeoh, Allen E J

    2007-03-01

    The introduction of the United Kingdom Medical Research Council's 10th AML trial (MRC AML 10) protocol incorporating high-dose anthracycline therapy has improved outcome of children with acute myeloid leukemia (AML). In this study, we review the results of childhood AML therapy in a Singapore university hospital over the last 17 years emphasizing toxicity and outcome. Retrospective analysis revealed 34 children with AML between 1988 and 2003. Prior to September 1996, therapy consisted of: POG-8498 (n = 10), others (n = 9). From September 1996, all but one of 15 children received MRC AML 10 treatment. At the time of analysis, 17 had died from disease, and 17 patients were alive among whom 2 had relapsed. MRC AML 10-treated patients (n = 14) had significantly better 3-year overall, event-free, and disease-free survival (74% vs. 35%, 77% vs. 20%, 83% vs. 31%; P = 0.019, P = 0.002, and P = 0.010, respectively) and were likelier to achieve complete remission (CR) than non-MRC AML 10 patients (P = 0.102). Among patients who achieved CR, MRC AML 10-treated patients were significantly more likely to achieve CR after only one cycle of chemotherapy (P = 0.016). Hematologic toxicity was similar among the different regimens (P = 0.9). These findings suggest that MRC AML 10 treatment results in significantly superior survival, without excess toxicity. Future studies should attempt to elucidate the relative importance of individual MRC AML 10 components and reduce the high cumulative anthracycline dose without compromising outcome. (c) 2006 Wiley-Liss, Inc.

  7. An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Ferguson, Paul; Hills, Robert K; Grech, Angela

    2016-01-01

    Up to 30% of adults with acute myeloid leukemia fail to achieve a complete remission after induction chemotherapy - termed primary refractory acute myeloid leukemia. There is no universally agreed definition of primary refractory disease, nor have the optimal treatment modalities been defined. We...... studied 8907 patients with newly diagnosed acute myeloid leukemia, and examined outcomes in patients with refractory disease defined using differing criteria which have previously been proposed. These included failure to achieve complete remission after one cycle of induction chemotherapy (RES), less than...... a 50% reduction in blast numbers with >15% residual blasts after one cycle of induction chemotherapy (REF1) and failure to achieve complete remission after two courses of induction chemotherapy (REF2). 5-year overall survival was decreased in patients fulfilling any criteria for refractory disease...

  8. Frequency of acute myeloid leukemia in children attended in Belém, Pará from August 2005 to May 2009

    OpenAIRE

    B. Junior,Lacy C.; Levy,Ian E.; Frances,Larissa Tatiana V. M.; Wanderley,Alayde V.; Carneiro,Rita de Cássia M.; Bentes,Alessandra Q.

    2015-01-01

    Introduction: Acute myeloid leukemia (AML) has variable incidence in different regions of Brazil. Objective: To determine the frequency of AML subtypes in children aged 0-17 years attended at Belém, Pará, from August 2005 to May 2009. Patients and methods: A retrospective study was performed with 278 patients diagnosed with acute or chronic leukemia based on clinical and morphological criteria (French-American-British [FAB]/World Health Organization classification [WHO]) and immunop...

  9. t(3;11)(q12;p15)/NUP98-LOC348801 fusion transcript in acute myeloid leukemia.

    Science.gov (United States)

    Gorello, Paolo; Brandimarte, Lucia; La Starza, Roberta; Pierini, Valentina; Bury, Loredana; Rosati, Roberto; Martelli, Massimo F; Vandenberghe, Peter; Wlodarska, Iwona; Mecucci, Cristina

    2008-09-01

    In a case of acute myeloid leukemia we report molecular cytogenetic findings of a t(3;11)(q12;p15), characterized as a new NUP98 translocation rearranging with LOC348801 at chromosome 3. NUP98 involvement was detected by fluorescence in situ hybridization. 3'-RACE-PCR showed nucleotide 1718 (exon 13) of NUP98 was fused in-frame with nucleotide 1248 (exon 2) of LOC348801. RT-PCR and cloning experiments detected two in-frame spliced NUP98-LOC348801 transcripts and the reciprocal LOC348801-NUP98. A highly specific double-color double-fusion FISH assay reliably detects NUP98-LOC348801.

  10. Practical Implications of the 2016 Revision of the World Health Organization Classification of Lymphoid and Myeloid Neoplasms and Acute Leukemia.

    Science.gov (United States)

    Leonard, John P; Martin, Peter; Roboz, Gail J

    2017-08-10

    A major revision of the WHO classification of lymphoid and myeloid neoplasms and acute leukemia was released in 2016. A key motivation for this update was to include new information available since the 2008 version with clinical relevance for the diagnosis, prognosis, and therapy of patients. With > 100 entities described, it is important for the clinician to understand features that may be important in daily practice, whereas researchers need to incorporate the new classification scheme into study development and analysis. In this review, we highlight the key aspects of the 2016 update with particular importance to routine patient care and clinical trial design.

  11. ABO incompatibility in mismatched unrelated donor allogeneic hematopoietic cell transplantation for acute myeloid leukemia: A report from the acute leukemia working party of the EBMT.

    Science.gov (United States)

    Canaani, Jonathan; Savani, Bipin N; Labopin, Myriam; Michallet, Mauricette; Craddock, Charles; Socié, Gerard; Volin, Lisa; Maertens, Johan A; Crawley, Charles; Blaise, Didier; Ljungman, Per T; Cornelissen, Jan; Russell, Nigel; Baron, Frédéric; Gorin, Norbert; Esteve, Jordi; Ciceri, Fabio; Schmid, Christoph; Giebel, Sebastian; Mohty, Mohamad; Nagler, Arnon

    2017-08-01

    ABO incompatibility is commonly observed in stem cell transplantation and its impact in this setting has been extensively investigated. HLA-mismatched unrelated donors (MMURD) are often used as an alternative stem cell source but are associated with increased transplant related complications. Whether ABO incompatibility affects outcome in MMURD transplantation for acute myeloid leukemia (AML) patients is unknown. We evaluated 1,013 AML patients who underwent MMURD transplantation between 2005 and 2014. Engraftment rates were comparable between ABO matched and mismatched patients, as were relapse incidence [34%; 95% confidence interval (CI), 28-39; for ABO matched vs. 36%; 95% CI, 32-40; for ABO mismatched; P = .32], and nonrelapse mortality (28%; 95% CI, 23-33; for ABO matched vs. 25%; 95% CI, 21-29; for ABO mismatched; P = .2). Three year survival was 40% for ABO matched and 43% for ABO mismatched patients (P = .35), Leukemia free survival rates were also comparable between groups (37%; 95% CI, 32-43; for ABO matched vs. 38%; 95% CI, 33-42; for ABO mismatched; P = .87). Incidence of grade II-IV acute graft versus host disease was marginally lower in patients with major ABO mismatching (Hazard ratio of 0.7, 95% CI, 0.5-1; P = .049]. ABO incompatibility probably has no significant clinical implications in MMURD transplantation. © 2017 Wiley Periodicals, Inc.

  12. Acute myeloid leukemia in the era of precision medicine: recent advances in diagnostic classification and risk stratification.

    Science.gov (United States)

    Kansal, Rina

    2016-03-01

    Acute myeloid leukemia (AML) is a genetically heterogeneous myeloid malignancy that occurs more commonly in adults, and has an increasing incidence, most likely due to increasing age. Precise diagnostic classification of AML requires clinical and pathologic information, the latter including morphologic, immunophenotypic, cytogenetic and molecular genetic analysis. Risk stratification in AML requires cytogenetics evaluation as the most important predictor, with genetic mutations providing additional necessary information. AML with normal cytogenetics comprises about 40%-50% of all AML, and has been intensively investigated. The currently used 2008 World Health Organization classification of hematopoietic neoplasms has been proposed to be updated in 2016, also to include an update on the classification of AML, due to the continuously increasing application of genomic techniques that have led to major advances in our knowledge of the pathogenesis of AML. The purpose of this review is to describe some of these recent major advances in the diagnostic classification and risk stratification of AML.

  13. Association of mutations with morphologic dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities.

    Science.gov (United States)

    Weinberg, Olga K; Gibson, Christopher J; Blonquist, Traci M; Neuberg, Donna; Pozdnyakova, Olga; Kuo, Frank; Ebert, Benjamin L; Hasserjian, Robert P

    2018-01-11

    Despite improvements in our understanding of the molecular basis of acute myeloid leukemia, the association between genetic mutations with morphologic dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow specimens from 168 patients with de novo acute myeloid leukemia; none of these patients had 2016 WHO Classification-defined cytogenetic abnormalities. We then performed targeted sequencing of diagnostic bone marrow aspirates for recurrent mutations associated with myeloid malignancies. We found that cohesin pathway mutations (q (FDR-adjusted p)=0.046) were associated with a higher degree of megakaryocytic dysplasia and STAG2 mutations were marginally associated with greater myeloid lineage dysplasia (q=0.052). Frequent megakaryocytes with separated nuclear lobes were more commonly seen among cases with cohesin pathway mutations (q=0.010) and specifically in those with STAG2 mutations (q=0.010), as well as NPM1 mutations (q=0.022 when considering the presence of any versus no megakaryocytes with separated nuclear lobes). RAS pathway mutations (q=0.006) and FLT3-ITD (q=0.006) were significantly more frequent in cases without evaluable erythroid cells. In univariate analysis of the 153 patients treated with induction chemotherapy, NPM1 mutations were associated with longer event-free survival (EFS, p=0.042), while RUNX1 (p=0.042), NF1 (p=0.040), frequent micromegakaryocytes (p=0.018) and presence of a subclone (p=0.002) were associated with shorter EFS. In multivariable modelling, NPM1 was associated with longer EFS, while presence of a subclone and frequent micromegakaryocytes remained significantly associated with shorter EFS. Copyright © 2018, Ferrata Storti Foundation.

  14. The potassium channel Ether à go-go is a novel prognostic factor with functional relevance in acute myeloid leukemia

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    Stühmer Walter

    2010-01-01

    Full Text Available Abstract Background The voltage-gated potassium channel hEag1 (KV10.1 has been related to cancer biology. The physiological expression of the human channel is restricted to the brain but it is frequently and abundantly expressed in many solid tumors, thereby making it a promising target for a specific diagnosis and therapy. Because chronic lymphatic leukemia has been described not to express hEag1, it has been assumed that the channel is not expressed in hematopoietic neoplasms in general. Results Here we show that this assumption is not correct, because the channel is up-regulated in myelodysplastic syndromes, chronic myeloid leukemia and almost half of the tested acute myeloid leukemias in a subtype-dependent fashion. Most interestingly, channel expression strongly correlated with increasing age, higher relapse rates and a significantly shorter overall survival. Multivariate Cox regression analysis revealed hEag1 expression levels in AML as an independent predictive factor for reduced disease-free and overall survival; such an association had not been reported before. As a functional correlate, specific hEag1 blockade inhibited the proliferation and migration of several AML cell lines and primary cultured AML cells in vitro. Conclusion Our observations implicate hEag1 as novel target for diagnostic, prognostic and/or therapeutic approaches in AML.

  15. [Expression of CD25 in Acute Myeloid Leukemia Is An Adverse Prognostic Factor Independent of the Chromosome Karyotype].

    Science.gov (United States)

    Liu, Yan-Fang; Dong, Li; Wang, Chong; Sun, Hui; Zhang, Qiu-Tang; Wang, Meng; Li, Tao; Xu, Yan; Ma, Jie; Xie, Xin-Sheng; Sun, Ling; Wan, Ding-Ming

    2016-04-01

    To investigate the CD25 expression in patients with acute myeloid leukemia (AML) and its significance. Clinical data of 168 newly diagnosed AML patients (except APL) were collected. The expression of CD25 in AML patients and its clinical characteristics were retrospectively analyzed. The leukemia cells of 29 out of 168 cases (17.26%) expressed CD25 antigen. Most of CD25 positive AML patients were occurred in patients with unfavourable or normal karyotype, higher WBC and Plt count at diagnosis and higher percentage of blasts in peripheral blood and bone marrow. Compared with CD25(-) AML patients, CD25(+) AML patients had lower CR rate (the CR rate of 1 course of treatment were 49.02% and 16.00%, respectively, P karyotype were not significantly different from that in patients with intermediate karyotype (P karyotype in terms of low complete remission rate and short survival time.

  16. A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species

    Directory of Open Access Journals (Sweden)

    Hongliang Zong

    2015-12-01

    Full Text Available Acute myeloid leukemia (AML is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90. Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy.

  17. Immunotherapy with natural killer cells: a possible approach for the treatment of Acute Myeloid Leukemia also in Brazil

    Directory of Open Access Journals (Sweden)

    Lúcia Silla

    Full Text Available SUMMARY The allogeneic hematopoietic stem cell transplantation (HSCT can cure intermediate and high-risk acute myeloid leukemia. Even with the development of strategies to reduce HSCT toxicity, this is still a complex treatment with high morbidity and mortality. Knowledge of the graft versus leukemia effect of HSCT has prepared the way for the development of Adoptive Immunotherapy or in vitro expansion of activated lymphocytes without alloreactivity, with subsequent intravenous infusion. The infusion of genetically modified T lymphocytes and haploidentical natural killer cells has been tested as an alternative to HSCT with very interesting results worldwide and in Brazil, as we not only have the technology of in vitro expansion of clinical grade lymphocytes available, but also do it according to the Good Manufacturing Practices that have been determined internationally.

  18. Mutation profiling of 19 candidate genes in acute myeloid leukemia suggests significance of DNMT3A mutations.

    Science.gov (United States)

    Shin, Sang-Yong; Lee, Seung-Tae; Kim, Hee-Jin; Cho, Eun Hae; Kim, Jong-Won; Park, Silvia; Jung, Chul Won; Kim, Sun-Hee

    2016-08-23

    We selected 19 significantly-mutated genes in AMLs, including FLT3, DNMT3A, NPM1, TET2, RUNX1, CEBPA, WT1, IDH1, IDH2, NRAS, ASXL1, SETD2, PTPN11, TP53, KIT, JAK2, KRAS, BRAF and CBL, and performed massively parallel sequencing for 114 patients with acute myeloid leukemias, mainly including those with normal karyotypes (CN-AML). More than 80% of patients had at least one mutation in the genes tested. DNMT3A mutation was significantly associated with adverse outcome in addition to conventional risk stratification such as the European LeukemiaNet (ELN) classification. We observed clinical usefulness of mutation testing on multiple target genes and the association with disease subgroups, clinical features and prognosis in AMLs.

  19. TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia.

    Science.gov (United States)

    Qian, Sixuan; Li, Jianyong; Hong, Ming; Zhu, Yu; Zhao, Huihui; Xie, Yue; Huang, Jiayu; Lian, Yun; Li, Yanru; Wang, Shuai; Mao, Jianping; Chen, Yaoyu

    2016-11-25

    Cancer cells show increased glycolysis and take advantage of this metabolic pathway to generate ATP. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits aerobic glycolysis and protects tumor cells from intracellular reactive oxygen species (ROS)-associated apoptosis. However, the function of TIGAR in glycolysis and survival of acute myeloid leukemia cells remains unclear. We analyzed TIGAR expression in cytogenetically normal (CN-) AML patients and the correlations with clinical and biological parameters. In vivo and in vitro, we tested whether glycolysis may induce TIGAR expression and evaluated the combination effect of glycolysis inhibitor and TIGAR knockdown on human leukemia cell proliferation. High TIGAR expression was an independent predictor of poor survival and high incidence of relapse in adult patients with CN-AML. TIGAR also showed high expression in multiple human leukemia cell lines and knockdown of TIGAR activated glycolysis through PFKFB3 upregulation in human leukemia cells. Knockdown of TIGAR inhibited the proliferation of human leukemia cells and sensitized leukemia cells to glycolysis inhibitor both in vitro and in vivo. Furthermore, TIGAR knockdown in combination with glycolysis inhibitor 2-DG led leukemia cells to apoptosis. In addition, the p53 activator Nutlin-3α showed a significant combinational effect with TIGAR knockdown in leukemia cells. However, TIGAR expression and its anti-apoptotic effects were uncoupled from overexpression of exogenous p53 in leukemia cells. TIGAR might be a predictor of poor survival and high incidence of relapse in AML patients, and the combination of TIGAR inhibitors with anti-glycolytic agents may be novel therapies for the future clinical use in AML patients.

  20. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission

    DEFF Research Database (Denmark)

    Nagler, Arnon; Rocha, Vanderson; Labopin, Myriam

    2013-01-01

    Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable bioavailabil......Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable...

  1. A mathematical model for leukemogenesis of radiation-induced acute myeloid leukemia in C3H/He mice

    International Nuclear Information System (INIS)

    Kai, M.; Ban, N.

    2002-01-01

    We developed a mathematical model in leukemogenesis of acute myeloid leukemia(AML) in C3H/He mice irradiated. Our previous study indicated that the leukemogenesis of AML was associated with a deletion of chromosome 2 directly induced by acute radiation. We hypothesized that radiation-induced AML needs both inactivation of one allele of a causative gene directly induced by acute radiation and another mutational event at the other allele. We analyzed data using a two-stage stochastic model for carcinogenesis. Model fitting was based on the maximum likelihood method. Our model analysis suggested that a single exposure might induce the long-lasting delayed cell death of radiation-induced initiated cells, and that the incidence of AML may be determined through both radiation-induced initiation and persistent increase of delayed cell death of the initiated cell induced by radiation

  2. Changes in magnetic resonance bone marrow angiogenesis on day 7 after induction chemotherapy can predict outcome of acute myeloid leukemia

    Science.gov (United States)

    Hou, Hsin-An; Shih, Tiffany Ting-Fang; Liu, Chieh-Yu; Chen, Bang-Bin; Tang, Jih-Luh; Yao, Ming; Huang, Shang-Yi; Chou, Wen-Chien; Hsu, Chao-Yu; Tien, Hwei-Fang

    2010-01-01

    Recently, dynamic contrast-enhanced magnetic resonance imaging has been shown to be a non-invasive technique that provides global and functional imaging of bone marrow angiogenesis in acute myeloid leukemia. To assess the clinical implication of changes in angiogenesis shortly after induction chemotherapy, dynamic contrast-enhanced magnetic resonance imaging was performed prospectively before treatment (day 0) and on day 7 in 80 patients with de novo acute myeloid leukemia. We demonstrated that a post-therapeutic reduction in Peak (negative ΔPeak) compared with the day 0 value was significantly associated with a higher chance of achieving complete remission, and better overall and disease free survival (P=0.022, 0.003 and 0.007, respectively). Cox’s multivariate analysis also identified negative ΔPeak value as an independent good prognostic factor for overall and disease free survival. Our findings provide evidence that the change of Peak on day 7 relative to pre-treatment levels may be a relevant biomarker for early identification of patients who may fail conventional induction chemotherapy (ClinicalTrials.gov Identifier: NCT00172562). PMID:20220062

  3. Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries.

    Science.gov (United States)

    Wennström, Lovisa; Edslev, Pernille Wendtland; Abrahamsson, Jonas; Nørgaard, Jan Maxwell; Fløisand, Yngvar; Forestier, Erik; Gustafsson, Göran; Heldrup, Jesper; Hovi, Liisa; Jahnukainen, Kirsi; Jonsson, Olafur Gisli; Lausen, Birgitte; Palle, Josefine; Zeller, Bernward; Holmberg, Erik; Juliusson, Gunnar; Stockelberg, Dick; Hasle, Henrik

    2016-01-01

    Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited. We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries. The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor. No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols. © 2015 Wiley Periodicals, Inc.

  4. Double minute chromosomes in acute myeloid leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia are associated with micronuclei, MYC or MLL amplification, and complex karyotype.

    Science.gov (United States)

    Huh, Yang O; Tang, Guilin; Talwalkar, Sameer S; Khoury, Joseph D; Ohanian, Maro; Bueso-Ramos, Carlos E; Abruzzo, Lynne V

    2016-01-01

    Double minute chromosomes (dmin) are small, paired chromatin bodies that lack a centromere and represent a form of extrachromosomal gene amplification. Dmin are rare in myeloid neoplasms and are generally associated with a poor prognosis. Most studies of dmin in myeloid neoplasms are case reports or small series. In the current study, we present the clinicopathologic and cytogenetic features of 22 patients with myeloid neoplasms harboring dmin. These neoplasms included acute myeloid leukemia (AML) (n = 18), myelodysplastic syndrome (MDS) (n = 3), and chronic myelomonocytic leukemia (CMML) (n = 1). The AML cases consisted of AML with myelodysplasia-related changes (n = 13) and therapy-related AML (n = 5). Dmin were detected in initial pre-therapy samples in 14 patients with AML or CMML; they were acquired during the disease course in 8 patients who had AML or MDS. The presence of dmin was associated with micronuclei (18/18; 100%), complex karyotype (17/22; 77.3%), and amplification of MYC (12/16; 75%) or MLL (4/16; 25%). Immunohistochemical staining for MYC performed on bone marrow core biopsy or clot sections revealed increased MYC protein in all 19 cases tested. Except for one patient, most patients failed to respond to risk-adapted chemotherapies. At last follow up, all patients had died of disease after a median of 5 months following dmin detection. In conclusion, dmin in myeloid neoplasms commonly harbor MYC or MLL gene amplification and manifest as micronuclei within leukemic blasts. Dmin are often associated with myelodysplasia or therapy-related disease, and complex karyotypes. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Phase I-II study of aclarubicin for treatment of acute myeloid leukemia.

    Science.gov (United States)

    Machover, D; Gastiaburu, J; Delgado, M; Goldschmidt, E; Hulhoven, R; Misset, J L; de Vassal, F; Tapiero, H; Ribaud, P; Schwarzenberg, L

    1984-06-01

    Aclarubicin (ACM) was administered as induction treatment to 40 patients with acute myeloid leukemia (AML) who were either refractory to initial induction chemotherapy or in relapse. Thirty-eight patients with AML, 2-80 years of age (mean +/- SE, 35.0 +/- 3.2), were evaluated during this study. Seventeen of these patients were given ACM after an unsuccessful attempt had been made to attain a complete remission (CR) with various regimens that included doxorubicin or daunorubicin; this group was considered resistant to these drugs. ACM was administered by rapid iv injection. Thirteen patients received a single course of ACM at a daily dose of 10-30 mg/m2 until a maximum total dose of 300 mg/m2 was reached or until unacceptable toxicity appeared. Of these patients, two (15%) attained a CR. The other 25 patients were given 10-day courses of ACM at a daily dose of 15 mg/m2 with 10-day intervals between courses; courses were repeated until the blast cells were cleared from peripheral blood and bone marrow or until progressive disease became evident. With this regimen, 11 patients (44%) attained a CR. The overall CR rate for the 38 patients was 34%. Total doses necessary to achieve a CR ranged from 150 to 600 mg/m2. A CR was attained by six patients who were previously resistant to a regimen containing moderate doses of doxorubicin. The incidence and severity of the toxic effects were related to the dose of ACM administered per course of therapy. The incidence of mucositis, diarrhea, vomiting, and infection in patients who received doses greater than 150 mg/m2/course was significantly higher than that observed in patients who received a dose of 150 mg/m2/course. In the latter patients, toxicity was within acceptable limits. Alopecia was not observed. Three patients had transient T-wave inversion, and reversible atrial flutter developed in one patient. Our results indicate that ACM is a major new drug for the treatment of AML.

  6. Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India

    Directory of Open Access Journals (Sweden)

    Abhijeet Ganapule

    2017-12-01

    Full Text Available Purpose: There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT for patients with acute myeloid leukemia (AML. Patients and Methods: We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results: Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%. The 5-year overall survival (OS and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1, second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively (P < .001. From 2007, reduced intensity conditioning (RIC with fludarabine and melphalan (Flu/Mel was used in a majority of patients in CR1 (n = 67. Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38. Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% (P = .003 and 63.8 ± 6.4% versus 32.3 ± 7.9% (P = .002, respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion: In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients.

  7. A Modified Integrated Genetic Model for Risk Prediction in Younger Patients with Acute Myeloid Leukemia.

    Science.gov (United States)

    Sloan, Caroline E; Luskin, Marlise R; Boccuti, Anne M; Sehgal, Alison R; Zhao, Jianhua; Daber, Robert D; Morrissette, Jennifer J D; Luger, Selina M; Bagg, Adam; Gimotty, Phyllis A; Carroll, Martin

    2016-01-01

    Although cytogenetics-based prognostication systems are well described in acute myeloid leukemia (AML), overall survival (OS) remains highly variable within risk groups. An integrated genetic prognostic (IGP) model using cytogenetics plus mutations in nine genes was recently proposed for patients ≤60 years to improve classification. This model has not been validated in clinical practice. We retrospectively studied 197 patients with newly diagnosed de novo AML. We compared OS curves among the mutational profiles defined by the IGP model. The IGP model assigned patients with intermediate cytogenetics as having favorable, intermediate or unfavorable mutational profiles. The IGP model reassigned 50 of 137 patients with intermediate cytogenetics to favorable or unfavorable mutational profiles. Median OS was 2.8 years among 14 patients with intermediate cytogenetics and favorable mutational profiles (mutant NPM1 and mutant IDH1 or IDH2) and 1.3 years among patients with intermediate mutational profiles. Among patients with intermediate cytogenetics labeled as having unfavorable mutational profiles, median OS was 0.8 years among 24 patients with FLT3-ITD positive AML and high-risk genetic changes (trisomy 8, TET2 and/or DNMT3A) and 1.7 years among 12 patients with FLT3-ITD negative AML and high-risk mutations (TET2, ASXL1 and/or PHF6). OS for patients with intermediate cytogenetics and favorable mutational profiles was similar to OS for patients with favorable cytogenetics (p = 0.697) and different from patients with intermediate cytogenetics and intermediate mutational profiles (p = 0.028). OS among patients with FLT3-ITD positive AML and high-risk genetic changes was similar to patients with unfavorable cytogenetics (p = 0.793) and different from patients with intermediate IGP profile (p = 0.022). Patients with FLT3-ITD negative AML and high-risk mutations, defined as 'unfavorable' in the IGP model, had OS similar to patients with intermediate IGP profile (p = 0

  8. Concurrent targeting Akt and sphingosine kinase 1 by A-674563 in acute myeloid leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Lin [Xiangya Hospital, Central South University, Changsha (China); Shaoyang Central Hospital, Hunan Province (China); Zhang, Yanan; Gao, Meng [The Third Xiangya Hospital, Central South University, Changsha, 410013 (China); Wang, Guangping, E-mail: wangguangping45@sina.com [Xiangya Hospital, Central South University, Changsha (China); Fu, Yunfeng, E-mail: fuyunfeng33163@163.com [The Third Xiangya Hospital, Central South University, Changsha, 410013 (China)

    2016-04-15

    Akt signaling plays a pivotal role in acute myeloid leukemia (AML) development and progression. In the present study, we evaluated the potential anti-AML activity by a novel Akt kinase inhibitor A-674563. Our results showed that A-674563 dose-dependently inhibited survival and proliferation of U937 AML cells and six lines of human AML progenitor cells, yet sparing human peripheral blood mononuclear leukocytes (PBMCs). A-674563 activated caspase-3/9 and apoptosis in the AML cells. Reversely, the pan-caspase inhibitor z-VAD-CHO dramatically alleviated A-674563-induced AML cell apoptosis and cytotoxicity. For the molecular study, we showed that A-674563 blocked Akt activation in U937 cells and human AML progenitor cells. Further, A-674563 decreased sphingosine kinase 1 (SphK1) activity in above AML cells to deplete pro-survival sphingosine-1-phosphate (S1P) and boost pro-apoptotic ceramide production. Such an effect on SphK1 signaling by A-674563 appeared independent of Akt blockage. Significantly, K6PC-5, a novel SphK1 activator, or supplement with S1P attenuated A-674563-induced ceramide production, and subsequent U937 cell death and apoptosis. Importantly, intraperitoneal injection of A-674563 at well-tolerated doses suppressed U937 leukemic xenograft tumor growth in nude mice, whiling significantly improving the animal survival. The results of the current study demonstrate that A-674563 exerts potent anti-leukemic activity in vitro and in vivo, possibly via concurrent targeting Akt and SphK1 signalings. - Highlights: • A-674563 is cytotoxic and anti-proliferative in U937 and AML progenitor cells. • A-674563 activates caspase-3/9 and apoptosis in U937 and AML progenitor cells. • Whiling blocking Akt, A-674563 manipulates other signalings in AML cells. • A-674563 inhibits SphK1 activity in AML cells, independent of Akt blockage. • A-674563 injection inhibits U937 xenograft in vivo growth, and improves mice survival.

  9. A Modified Integrated Genetic Model for Risk Prediction in Younger Patients with Acute Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Caroline E Sloan

    Full Text Available Although cytogenetics-based prognostication systems are well described in acute myeloid leukemia (AML, overall survival (OS remains highly variable within risk groups. An integrated genetic prognostic (IGP model using cytogenetics plus mutations in nine genes was recently proposed for patients ≤60 years to improve classification. This model has not been validated in clinical practice.We retrospectively studied 197 patients with newly diagnosed de novo AML. We compared OS curves among the mutational profiles defined by the IGP model. The IGP model assigned patients with intermediate cytogenetics as having favorable, intermediate or unfavorable mutational profiles. The IGP model reassigned 50 of 137 patients with intermediate cytogenetics to favorable or unfavorable mutational profiles. Median OS was 2.8 years among 14 patients with intermediate cytogenetics and favorable mutational profiles (mutant NPM1 and mutant IDH1 or IDH2 and 1.3 years among patients with intermediate mutational profiles. Among patients with intermediate cytogenetics labeled as having unfavorable mutational profiles, median OS was 0.8 years among 24 patients with FLT3-ITD positive AML and high-risk genetic changes (trisomy 8, TET2 and/or DNMT3A and 1.7 years among 12 patients with FLT3-ITD negative AML and high-risk mutations (TET2, ASXL1 and/or PHF6. OS for patients with intermediate cytogenetics and favorable mutational profiles was similar to OS for patients with favorable cytogenetics (p = 0.697 and different from patients with intermediate cytogenetics and intermediate mutational profiles (p = 0.028. OS among patients with FLT3-ITD positive AML and high-risk genetic changes was similar to patients with unfavorable cytogenetics (p = 0.793 and different from patients with intermediate IGP profile (p = 0.022. Patients with FLT3-ITD negative AML and high-risk mutations, defined as 'unfavorable' in the IGP model, had OS similar to patients with intermediate IGP profile (p

  10. Overexpression of Wilms Tumor 1 Gene as a Negative Prognostic Indicator in Acute Myeloid Leukemia

    Science.gov (United States)

    Mi, Ruihua; Ding, Jing; Wang, Xianwei; Hu, Jieying; Fan, Ruihua; Wei, Xudong; Song, Yongping; Zhao, Richard Y.

    2014-01-01

    Chromosomal aberrations are useful in assessing treatment options and clinical outcomes of acute myeloid leukemia (AML) patients. However, 40∼50% of the AML patients showed no chromosomal abnormalities, i.e., with normal cytogenetics aka the CN-AML patients. Testing of molecular aberrations such as FLT3 or NPM1 can help to define clinical outcomes in the CN-AML patients but with various successes. Goal of this study was to test the possibility of Wilms’ tumor 1 (WT1) gene overexpression as an additional molecular biomarker. A total of 103 CN-AML patients, among which 28% had overexpressed WT1, were studied over a period of 38 months. Patient’s response to induction chemotherapy as measured by the complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were measured. Our data suggested that WT1 overexpression correlated negatively with the CR rate, DFS and OS. Consistent with previous reports, CN-AML patients can be divided into three different risk subgroups based on the status of known molecular abnormalities, i.e., the favorable (NPM1mt/no FLT3ITD), the unfavorable (FLT3ITD) and the intermediate risk subgroups. The WT1 overexpression significantly reduced the CR, DFS and OS in both the favorable and unfavorable groups. As the results, patients with normal WT1 gene expression in the favorable risk group showed the best clinical outcomes and all survived with complete remission and disease-free survival over the 37 month study period; in contrast, patients with WT1 overexpression in the unfavorable risk group displayed the worst clinical outcomes. WT1 overexpression by itself is an independent and negative indicator for predicting CR rate, DFS and OS of the CN-AML patients; moreover, it increases the statistical power of predicting the same clinical outcomes when it is combined with the NPM1 mt or the FLT3 ITD genotypes that are the good or poor prognostic markers of CN-AML. PMID:24667279

  11. Prognostic impact of Wilms tumor gene mutations in Egyptian patients with acute myeloid leukemia with normal karyotype.

    Science.gov (United States)

    Zidan, Magda Abdel Aziz; Kamal Shaaban, Howyda M; Elghannam, Doaa M

    2014-07-01

    The Wilms' tumor (WT1) gene mutations were detected in patients with most forms of acute leukemia. However, the biological significance and the prognostic impact of WT1 mutation in Egyptian patients with acute myeloid leukemia with normal karyotype (AML-NK) are still uncertain. We aimed to evaluate the incidence and clinical relevance of WT1 gene mutations in acute myeloid leukemia with normal karyotype (AML-NK). Exons 7 and 9 of WT1 were screened in samples from 216 adult NK-AML using polymerase chain reaction single-strand conformation polymorphism techniques. Twenty-three patients (10.6%) harbored WT1 mutations. Younger ages and higher marrow blasts were significantly associated with WT1 mutations (P = 0.006 and 0.003 respectively). Complete remission rates were significantly lower in patients with WT1 mutations than those with WT1 wild-type (P = 0.015). Resistance, relapse, and mortality rates were significantly higher in patients with WT1 mutations than those without (P = 0.041, 0.016, and 0.008 respectively). WT1 mutations were inversely associated with NPM1 mutations (P = 0.007). Patients with WT1 mutations had worse disease-free survival (P < 0.001) and overall survival (P < 0.001) than patients with WT1 wild-type. In multivariable analyses, WT1 mutations independently predicted worse DFS (P < 0.001; hazard ratio [HR] 0.036) and overall survival (P = 0.001; HR = 0.376) when controlling for age, total leukocytic count (TLC), and NPM1 mutational status. In conclusion, WT1 mutations are a negative prognostic indicator in intensively treated patients with AML-NK, may be a part of molecularly based risk assessment and risk-adapted treatment stratification of patients with AML-NK.

  12. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

    NARCIS (Netherlands)

    T. Pabst (Thomas); E. Vellenga (Edo); W.L.J. van Putten (Wim); H. Schouten (Harry); C. Graux (Carlos); M.-C. Vekemans (Marie-Christiane); B.J. Biemond (Bart); P. Sonneveld (Pieter); J. Passweg (Jakob Robert); L.F. Verdonck (Leo); M.C.J.C. Legdeur (M. C J C); M. Theobald (Matthias); E. Jacky (Emanuel); M. Bargetzi (Mario); J. Maertens (Johan); G.J. Ossenkoppele (Gert); B. Löwenberg (Bob)

    2012-01-01

    textabstractThe clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose

  13. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

    NARCIS (Netherlands)

    Pabst, Thomas; Vellenga, Edo; van Putten, Wim; Schouten, Harry C.; Graux, Carlos; Vekemans, Marie-Christiane; Biemond, Bart; Sonneveld, Peter; Passweg, Jakob; Verdonck, Leo; Legdeur, Marie-Cecile; Theobald, Matthias; Jacky, Emanuel; Bargetzi, Mario; Maertens, Johan; Ossenkoppele, Gert Jan; Lowenberg, Bob

    2012-01-01

    The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of

  14. Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia

    NARCIS (Netherlands)

    Lowenberg, B; Boogaerts, MA; Daenen, SMGJ; Verhoef, GEG; Hagenbeek, A; Vellenga, E; Ossenkoppele, GJ; Huijgens, PC; Verdonck, LF; vanderLelie, J; Wielenga, JJ; Gmur, J; Gratwohl, A; Hess, U; Fey, MF; vanPutten, WLJ

    1997-01-01

    Purpose: The hematopoietic growth factors (HGFs) introduced into induction chemotherapy (CT) of acute myeloid leukemia (AML) might be of benefit to treatment outcome by at least two mechanisms. HGFs given on days simultaneously with CT might sensitize the leukemic cells and enhance their

  15. MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia | Office of Cancer Genomics

    Science.gov (United States)

    Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction.

  16. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

    DEFF Research Database (Denmark)

    Möllgård, Lars; Saft, Leonie; Treppendahl, Marianne Bach

    2011-01-01

    Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization...

  17. Vascular endothelial growth factor secretion is an independent prognostic factor for relapse-free survival in pediatric acute myeloid leukemia patients

    NARCIS (Netherlands)

    de Bont, ESJM; Fidler, [No Value; Meeuwsen, T; Scherpen, F; Hahlen, K; Kamps, WA

    Substantial improvements in long-term survival have been made with acute myeloid leukemia (AML). However, the overall success rate in treatment of AML is around 50%, despite intensive chemotherapeutic regimens. AML cell survival seems to be related to vascular endothelial growth factor (VEGF). The

  18. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia

    NARCIS (Netherlands)

    B. Löwenberg (Bob); P. Muus (P.); G.J. Ossenkoppele (Gert); P. Rousselot (Philippe); J.-Y. Cahn (Jean-Yves); N. Ifrah (Norbert); G. Martinelli (Giovanni); S. Amadori (Sergio); E. Berman (Ellin); P. Sonneveld (Pieter); M. Jongen-Lavrencic (Mojca); S. Rigaudeau (Sophie); P. Stockman (Paul); D. Goudie (David); S. Faderl (Stefan); J. Jabbour (Jason); H. Kantarjian (Hagop)

    2011-01-01

    textabstractThe primary objective of this 2-part phase 1/2 study was to determine the maximum-tolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of

  19. Bortezomib sensitivity of acute myeloid leukemia CD34(+) cells can be enhanced by targeting the persisting activity of NF-kappa B and the accumulation of MCL-1

    NARCIS (Netherlands)

    Bosman, Matthieu Cornelis Johannes; Schuringa, Jan Jacob; Quax, Wilhelmus Johannes; Vellenga, Edo

    Sustained NF-kappa B activation is often observed in acute myeloid leukemia (AML); therefore, proteasome inhibition has been proposed to efficiently target AML cells. In this study, we questioned whether leukemic stem cell-enriched CD34(+) cells are sensitive to the proteasome inhibitor bortezomib.

  20. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10.

    NARCIS (Netherlands)

    Mandelli, F.; Vignetti, M.; Suciu, S.; Stasi, R.; Petti, M.C.; Meloni, G.; Muus, P.; Marmont, F.; Marie, J.P.; Labar, B.; Thomas, X.; Raimondo, F. Di; Willemze, R.; Liso, V.; Ferrara, F.; Baila, L.; Fazi, P.; Zittoun, R.; Amadori, S.; Witte, T.J.M. de

    2009-01-01

    PURPOSE: To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). PATIENTS AND METHODS: We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive

  1. Allium compounds, dipropyl and dimethyl thiosulfinates as antiproliferative and differentiating agents of human acute myeloid leukemia cell lines

    Directory of Open Access Journals (Sweden)

    Faten Merhi

    2008-08-01

    Full Text Available Faten Merhi1, Jacques Auger2, Francine Rendu1, Brigitte Bauvois11UMR 7131 UPMC Paris Universitas/CNRS, Groupe Hospitalier Broussais-HEGP, Paris, France; 2University F. Rabelais, IRBI, UPRESA CNRS 6035, Tours, FranceAbstract: Epidemiologic studies support the premise that Allium vegetables may lower the risk of cancers. The beneficial effects appear related to the organosulfur products generated upon processing of Allium. Leukemia cells from patients with acute myeloid leukemia (AML display high proliferative capacity and have a reduced capacity of undergoing apoptosis and maturation. Whether the sulfur-containing molecules thiosulfinates (TS, diallyl TS (All2TS, dipropyl TS (Pr2TS and dimethyl TS (Me2TS, are able to exert chemopreventative activity against AML is presently unknown. The present study was an evaluation of proliferation, cytotoxicity, differentiation and secretion of AML cell lines (U937, NB4, HL-60, MonoMac-6 in response to treatment with these TS and their related sulfides (diallylsulfide, diallyl disulfide, dipropyl disulfide, dimethyl disulfide. As assessed by flow cytometry, ELISA, gelatin zymogaphy and RT-PCR, we showed that Pr2TS and Me2TS, but not All2TS and sulfides, 1 inhibited cell proliferation in dose- and time-dependent manner and this process was neither due to cytotoxicity nor apoptosis, 2 induced macrophage maturation, and 3 inhibited the levels of secreted MMP-9 (protein and activity and TNF-α protein, without altering mRNA levels. By establishing for the first time that Pr2TS and Me2TS affect proliferation, differentiation and secretion of leukemic cell lines, this study provides the opportunity to explore the potential efficiency of these molecules in AML.Keywords: acute myeloid leukemia, thiosulfinate, proliferation, differentiation, matrix metalloproteinase-9

  2. Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

    Science.gov (United States)

    Mohty, Mohamad; Malard, Florent; Blaise, Didier; Milpied, Noel; Socié, Gérard; Huynh, Anne; Reman, Oumédaly; Yakoub-Agha, Ibrahim; Furst, Sabine; Guillaume, Thierry; Tabrizi, Resa; Vigouroux, Stéphane; Peterlin, Pierre; El-Cheikh, Jean; Moreau, Philippe; Labopin, Myriam; Chevallier, Patrice

    2017-01-01

    The prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients’ outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33–71) at 1 year and 38% (95% CI: 18–46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26–64) at 1 year and 29% (95% CI: 13–48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1–24) at 1 year and 12% (95% CI: 3–19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174. PMID:27561720

  3. Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Eduardo Laborda

    2017-10-01

    Full Text Available The treatment of patients with acute myeloid leukemia (AML with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR-engineered T-cells (CAR-T-cells, a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs, and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.

  4. Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia.

    Science.gov (United States)

    Qian, Zhijian; Fernald, Anthony A; Godley, Lucy A; Larson, Richard A; Le Beau, Michelle M

    2002-11-12

    One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34(+) hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding IFN consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of urgently needed targeted therapies.

  5. Oncogenic RAS enables DNA damage- and p53-dependent differentiation of acute myeloid leukemia cells in response to chemotherapy.

    Directory of Open Access Journals (Sweden)

    Mona Meyer

    Full Text Available Acute myeloid leukemia (AML is a clonal disease originating from myeloid progenitor cells with a heterogeneous genetic background. High-dose cytarabine is used as the standard consolidation chemotherapy. Oncogenic RAS mutations are frequently observed in AML, and are associated with beneficial response to cytarabine. Why AML-patients with oncogenic RAS benefit most from high-dose cytarabine post-remission therapy is not well understood. Here we used bone marrow cells expressing a conditional MLL-ENL-ER oncogene to investigate the interaction of oncogenic RAS and chemotherapeutic agents. We show that oncogenic RAS synergizes with cytotoxic agents such as cytarabine in activation of DNA damage checkpoints, resulting in a p53-dependent genetic program that reduces clonogenicity and increases myeloid differentiation. Our data can explain the beneficial effects observed for AML patients with oncogenic RAS treated with higher dosages of cytarabine and suggest that induction of p53-dependent differentiation, e.g. by interfering with Mdm2-mediated degradation, may be a rational approach to increase cure rate in response to chemotherapy. The data also support the notion that the therapeutic success of cytotoxic drugs may depend on their ability to promote the differentiation of tumor-initiating cells.

  6. Acute myeloid leukemia with RAM immunophenotype: a pediatric case with unusual morphologic features

    Directory of Open Access Journals (Sweden)

    Miriam Conces

    2017-06-01

    Full Text Available The RAM immunophenotype has been recently described as a subtype of acute myelogenous leukemia (AML that is characterized clinically by extremely poor prognosis. We present a case of AML with RAM immunophenotype in a 5-year-old patient that resulted in poor outcome despite early hematopoietic cell transplant. We describe the unusual morphologic features that, along with the distinct immunophenotype, may provide initial diagnostic clues and further justify the classification of this AML variant as a rather distinct subtype.

  7. l-Asparaginase-mediated downregulation of c-Myc promotes 1,25(OH)2 D3 -induced myeloid differentiation in acute myeloid leukemia cells.

    Science.gov (United States)

    Song, Ju Han; Park, Eunchong; Kim, Myun Soo; Cho, Kyung-Min; Park, Su-Ho; Lee, Arim; Song, Jiseon; Kim, Hyeoung-Joon; Koh, Jeong-Tae; Kim, Tae Sung

    2017-05-15

    Treatment of acute myeloid leukemia (AML) largely depends on chemotherapy, but current regimens have been unsatisfactory for long-term remission. Although differentiation induction therapy utilizing 1,25(OH) 2 D 3 (VD3) has shown great promise for the improvement of AML treatment efficacy, severe side effects caused by its supraphysiological dose limit its clinical application. Here we investigated the combinatorial effect of l-asparaginase (ASNase)-mediated amino acid depletion and the latent alternation of VD3 activity on the induction of myeloid differentiation. ASNase treatment enhanced VD3-driven phenotypic and functional differentiation of three-different AML cell lines into monocyte/macrophages, along with c-Myc downregulation. Using gene silencing with shRNA and a chemical blocker, we found that reduced c-Myc is a critical factor for improving VD3 efficacy. c-Myc-dependent inhibition of mTORC1 signaling and induction of autophagy were involved in the enhanced AML cell differentiation. In addition, in a postculture of AML cells after each treatment, ASNase supports the antileukemic effect of VD3 by inhibiting cell growth and inducing apoptosis. Finally, we confirmed that the administration of ASNase significantly improved VD3 efficacy in the prolongation of survival time in mice bearing tumor xenograft. Our results are the first to demonstrate the extended application of ASNase, which is currently used for acute lymphoid leukemia, in VD3-mediated differentiation induction therapy for AML, and suggest that this drug combination may be a promising novel strategy for curing AML. © 2017 UICC.

  8. [Acute myeloid leukemia with bone marrow erythroblastosis: about one case illustrating the new WHO classification (2008)].

    Science.gov (United States)

    Vincenot, Anne; Abarah, Wajed; Frayfer, Jamilé; Mahfouz, Imad; Andre-Kerneis, Elisabeth

    2011-01-01

    We reported here a case of acute myeloid leukaemia (AML) in a 28-year-old male patient, which diagnosis is discussed according to the different classifications. This case focused on some new criteria and changes in the new WHO classification (2008) of AML, especially when erythroid precursors represent over 50% of bone marrow nucleated cells. It also pointed on some gene mutations (NPM1, CEPBA, FLT3, WT1…) and their prognostic features in AML with a normal karyotype, leading to individualize two new provisional entities in the WHO classification of tumours of hematopoietic and lymphoid tissues 2008.

  9. Mesenchymal stromal cells from patients with acute myeloid leukemia have altered capacity to expand differentiated hematopoietic progenitors.

    Science.gov (United States)

    Chandran, Priya; Le, Yevgeniya; Li, Yuhua; Sabloff, Mitchell; Mehic, Jelica; Rosu-Myles, Michael; Allan, David S

    2015-04-01

    The bone marrow microenvironment may be permissive to the emergence and progression of acute myeloid leukemia (AML). Studying interactions between the microenvironment and leukemia cells should provide new insight for therapeutic advances. Mesenchymal stromal cells (MSCs) are central to the maintenance of the hematopoietic niche. Here we compared the functions and gene expression patterns of MSCs derived from bone marrow aspirates of healthy donors and patients with AML. MSCs expanded from AML patients had heterogeneous morphology and displayed a wide range of proliferation capacity compared to MSCs from healthy controls. The ability of AML-MSCs to support the expansion of committed hematopoietic progenitors from umbilical cord blood-derived CD34+ cells may be impaired while the expression of genes associated with maintaining hematopoietic quiescence appeared to be increased in AML-MSCs compared to healthy donors. These results highlight important potential differences in the biologic profile of MSCs from AML patients compared to healthy donors that may contribute to the emergence or progression of leukemia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.

    Science.gov (United States)

    Pan, Rongqing; Hogdal, Leah J; Benito, Juliana M; Bucci, Donna; Han, Lina; Borthakur, Gautam; Cortes, Jorge; DeAngelo, Daniel J; Debose, Lakeisha; Mu, Hong; Döhner, Hartmut; Gaidzik, Verena I; Galinsky, Ilene; Golfman, Leonard S; Haferlach, Torsten; Harutyunyan, Karine G; Hu, Jianhua; Leverson, Joel D; Marcucci, Guido; Müschen, Markus; Newman, Rachel; Park, Eugene; Ruvolo, Peter P; Ruvolo, Vivian; Ryan, Jeremy; Schindela, Sonja; Zweidler-McKay, Patrick; Stone, Richard M; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina; Letai, Anthony G

    2014-03-01

    B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.

  11. Autologous bone marrow transplantation in acute myeloid leukemia: the university of minnesota experience

    International Nuclear Information System (INIS)

    Dusenbery, Kathryn E.; Steinbuch, Michael; McGlave, Philip B.; Ramsay, Norma K.C.; Blazar, Bruce R.; Neglia, Joseph P.; Litz, Craig; Kersey, John H.; Woods, William G.

    1996-01-01

    Purpose: To report the outcome of autologous bone marrow transplantation for patients with acute myeloid leukemia (AML) in first or greater complete remission (CR) treated by autologous bone marrow transplantation using two different preparatory regimens. Methods and Materials: Between September 1986 and August 1993, 75 patients with AML ranging in age from 6 months to 58 years underwent autologous bone marrow transplantation using previously harvested and frozen unpurged (n = 6) or 4-hydroperoxycyclophosphamide purged marrows (n = 69). Patients were in first CR (n = 44) or beyond first CR (n 31). The preparative regimen consisted of 120 mg/kg of cyclophosphamide (CY) and 1320 cGy total body irradiation (TBI) in eight fractions over 4 days (CY/TBI) in 29 patients; and 16 mg/kg of Busulfan (BU) and 200 mg/kg of CY (BU/CY) in 46 patients. Thirty-five of these 75 patients (18 CY/TBI and 17 BU/CY) were part of a randomized trial comparing the two preparative regimens. Results: At 2 years, overall survival and disease-free survival (DFS) were 49% [95% confidence interval (C.I.) 37-61%] and 43% (95% C.I. 32-55%), respectively. Patients in first CR had a significantly better outcome than patients beyond first CR with an estimated 2-year DFS of 59% (95% C.I. 44-74%) vs. 21% (95% C.I. 5-36%, log-rank p = 0.0001), respectively. For patients conditioned with CY/TBI, the estimated 2-year DFS was 52% compared to 39% for BU/CY (log-rank p = 0.35). Estimated 2-year relapse rates were 44% vs. 56% (log-rank p = 0.40), respectively. For patients in first CR, no differences in DFS were observed between the two regimens (2-year estimates 69% vs. 55% log-rank p = 0.52). Patients beyond first CR had a significantly improved DFS with the CY/TBI regimen (2-year estimates of 38% vs. 7%, log-rank p = 0.04). No differences were found between the two regimens in terms of time to WBC engraftment, absolute neutrophil count of gr 500, incidence of bacteremias, or median time to hospital

  12. Granulocytic Sarcoma of the Orbit Presenting as a Fulminant Orbitopathy in an Adult With Acute Myeloid Leukemia.

    Science.gov (United States)

    O'Neill, John P; Harrison, Andrew R; Cameron, J Douglas; Mokhtarzadeh, Ali

    A 64-year-old woman with relapsed acute myelogenous leukemia (AML) undergoing salvage chemotherapy developed rapid onset of right-sided ophthalmoplegia, proptosis, optic neuropathy, and vision loss from 20/30 to hand motions over a 3-hour period on day 4 of her treatment. CT scan of her orbits revealed a superolateral orbital mass and periocular edema. She underwent immediate canthotomy and cantholysis, and lateral orbitotomy with debulking of the mass later the same day. The histopathology was consistent with aggregates of myeloid blasts. Her vision recovered to 20/20 on postoperative day 1. Orbital granulocytic sarcoma is a rare condition often concurrent with AML, typically in the pediatric population and rarely in adults. Presentation as a fulminant orbitopathy with rapidly progressive optic neuropathy and vision loss over several hours has not been previously reported.

  13. Prophylactic administration of voriconazole with two different doses for invasive fungal infection in children and adolescents with acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Hirozumi Sano

    2018-04-01

    Full Text Available Background: Pediatric patients under treatment for acute myeloid leukemia (AML are at high risk for invasive fungal infection (IFI. We evaluated the efficacy of prophylactic administration of voriconazole (VRCZ with two different doses. Methods: Between October 2005 and June 2011, 17 children and adolescents (aged 0–20 years undergoing chemotherapy for AML were prophylactically administered with 5 mg/kg/d of oral VRCZ. Furthermore, 22 AML patients (aged 0–19 years were administered 10 mg/kg/d of oral VRCZ between July 2011 and December 2014. The incidences of IFI with two different doses of VRCZ were compared. Results: Irrespective of the dosage of VRCZ, eight patients developed IFI. Of these eight patients, four belonged to the 5 mg/kg/d group and four to the 10 mg/kg/d group. Cumulative incidences of IFI at 180 days after the initiation of chemotherapy were not different between the 5 mg/kg/d and 10 mg/kg/d groups. The trough plasma VRCZ concentration in the 10 mg/kg/d group ranged from < 0.09 μg/mL to 2.17 μg/mL, with a median level of 0.27 μg/mL, and patients with the targeted trough concentration (1–4 μg/mL comprised only 18.8% of the evaluable patients in this group, whereas the trough plasma VRCZ concentration of the evaluable patients in the 5 mg/kg/d group were all below the limit of sensitivity (< 0.09 μg/mL. Conclusion: More dose escalation is required based on this study. As VRCZ concentration is considerably influenced by genetic polymorphisms and drug–drug interactions, VRCZ should be used under therapeutic drug monitoring to keep effective drug concentrations. Keywords: acute myeloid leukemia, concentration, invasive fungal infection, prophylaxis, voriconazole

  14. Identification and validation of potential prognostic gene biomarkers for predicting survival in patients with acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Huang R

    2017-11-01

    Full Text Available Rui Huang,1,* Xiwen Liao,2,* Qiaochuan Li1 1Department of Hematology, 2Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China *These authors contributed equally to this work Background: Molecular analysis is a promising source of clinically useful prognostic biomarkers. The aim of this investigation was to identify prognostic biomarkers for patients with acute myeloid leukemia (AML by using the gene expression profile dataset from public database. Methods: The gene expression profile dataset and corresponding overall survival (OS information of three cohorts of AML patients from GSE12417 and The Cancer Genome Atlas AML project (TCGA-LAML were included in the present study. Prognostic gene screening was performed by using a survival package, whereas time-dependent receiver operating characteristic (ROC curve analysis was performed using the survivalROC package. Results: In the three cohorts, 11 genes were identified that were significantly associated with AML OS. A linear prognostic model of the 11 genes was constructed and weighted by regression coefficient (β from the multivariate Cox regression analyses of GSE12417 HG-U133A cohort to divide patients into high- and low-risk groups. GSE12417 HG-U133 plus 2.0 and TCGA-LAML were validation cohorts. Patients assigned to the high-risk group exhibited poor OS compared to patients in the low-risk group. The 11-gene signature is a prognostic marker of AML and demonstrates good performance for predicting 1-, 3-, and 5-year OS as evaluated by survivalROC in the three cohorts. Conclusion: Our study has identified an mRNA signature including 11 genes, which may serve as a potential prognostic marker of AML. Keywords: acute myeloid leukemia, prognosis, biomarker, GEO, TCGA

  15. A comprehensive review of occupational and general population cancer risk: 1,3-Butadiene exposure-response modeling for all leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myeloid neoplasm and lymphoid neoplasm.

    Science.gov (United States)

    Sielken, Robert L; Valdez-Flores, Ciriaco

    2015-11-05

    Excess cancer risks associated with 1,3-butadiene (BD) inhalation exposures are calculated using an extensive data set developed by the University of Alabama at Birmingham (UAB) from an epidemiology study of North American workers in the styrene butadiene rubber (SBR) industry. While the UAB study followed SBR workers, risk calculations can be adapted to estimate both occupational and general population risks. The data from the UAB SBR study offer an opportunity to quantitatively evaluate the association between cumulative exposure to BD and different types of cancer, accounting for the number of tasks involving high-intensity exposures to BD as well as confounding associated with the exposures to the multiple other chemicals in the SBR industry. Quantitative associations of BD exposure and cancer, specifically leukemia, can be further characterized by leukemia type, including potential associations with acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), and the groups of lymphoid and myeloid neoplasms. Collectively, these multiple evaluations lead to a comprehensive analysis that makes use of all of the available information and is consistent with the risk assessment goals of the USEPA and other regulatory agencies, and in line with the recommendations of the USEPA Science Advisory Board. While a range of cancer risk values can result from these multiple factors, a preferred case for occupational and general population risk is highlighted. Cox proportional hazards models are used to fit exposure-response models to the most recent UAB data. The slope of the model with cumulative BD ppm-years as the predictor variable is not statistically significantly greater than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined. The slope for CLL is statistically significantly different from zero. The slope for myeloid neoplasms is not statistically

  16. Potentially functional polymorphism in IL-23 receptor and risk of acute myeloid leukemia in a Chinese population.

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    Xifeng Qian

    Full Text Available The interleukin-23 (IL-23 and its receptor (IL-23R mediate the direct antitumor activities in human hematologic malignancies including pediatric acute leukemia. Two potentially functional genetic variants (IL-23R rs1884444 T>G and rs6682925 T>C have been found to contribute to solid cancer susceptibility. In this study, we conducted a case-control study including 545 acute myeloid leukemia (AML patients and 1,146 cancer-free controls in a Chinese population to assess the association between these two SNPs and the risk of AML. We found that IL-23R rs1884444 TG/GG and rs6682925 TC/CC variant genotypes were associated with significantly increased risk of AML [rs1884444: adjusted odds ratio (OR = 1.28, 95% confidence interval (CI = 1.01-1.62; rs6682925: adjusted OR = 1.30, 95%CI = 1.01-1.67], compared to their corresponding wild-type homozygotes, respectively. These findings indicated that genetic variants in IL-23R may contribute to AML risk in our Chinese population.

  17. A Case of Acute Myeloid Leukemia with a Previously Unreported Translocation (14; 15 (q32; q13

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    Mohamad Khawandanah

    2014-01-01

    Full Text Available Background. We hereby describe what we believe to be the first reported case of t (14; 15 (q32; q13 associated with acute myeloid leukemia (AML. Methods. PubMed, Embase, and OVID search engines were used to review the related literature and similar published cases. Case. A47-year-old female presented in December 2011 with AML (acute myelomonocytic leukemia with normal cytogenetics; molecular testing revealed FLT-3 internal tandem duplication (ITD mutation, while no mutations involving FLT3 D385/I836, NPM1 exon 12, or KIT exons 8 and 17 were detected. She was induced with 7 + 3 (cytarabine + idarubicin and achieved complete remission after a second induction with high-dose cytarabine (HiDAC followed by uneventful consolidation. She presented 19 months after diagnosis with relapsed disease. Of note, at relapse cytogenetic analysis revealed t (14; 15 (q32; q13, while FLT-3 analysis showed a codon D835 mutation (no ITD mutation was detected. She proved refractory to the initial clofarabine-based regimen, so FLAG-idarubicin then was used. She continued to have persistent disease, and she was discharged on best supportive care. Conclusion. Based on this single case of AML with t (14; 15 (q32; q13, this newly reported translocation may be associated with refractory disease.

  18. A Case of Acute Myeloid Leukemia with a Previously Unreported Translocation (14; 15) (q32; q13).

    Science.gov (United States)

    Khawandanah, Mohamad; Gehrs, Bradley; Li, Shibo; Holter Chakrabarty, Jennifer; Cherry, Mohamad

    2014-01-01

    Background. We hereby describe what we believe to be the first reported case of t (14; 15) (q32; q13) associated with acute myeloid leukemia (AML). Methods. PubMed, Embase, and OVID search engines were used to review the related literature and similar published cases. Case. A47-year-old female presented in December 2011 with AML (acute myelomonocytic leukemia) with normal cytogenetics; molecular testing revealed FLT-3 internal tandem duplication (ITD) mutation, while no mutations involving FLT3 D385/I836, NPM1 exon 12, or KIT exons 8 and 17 were detected. She was induced with 7 + 3 (cytarabine + idarubicin) and achieved complete remission after a second induction with high-dose cytarabine (HiDAC) followed by uneventful consolidation. She presented 19 months after diagnosis with relapsed disease. Of note, at relapse cytogenetic analysis revealed t (14; 15) (q32; q13), while FLT-3 analysis showed a codon D835 mutation (no ITD mutation was detected). She proved refractory to the initial clofarabine-based regimen, so FLAG-idarubicin then was used. She continued to have persistent disease, and she was discharged on best supportive care. Conclusion. Based on this single case of AML with t (14; 15) (q32; q13), this newly reported translocation may be associated with refractory disease.

  19. Total Body Irradiation without Chemotherapy as Conditioning for an Allogeneic Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia

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    Sultan Altouri

    2016-01-01

    Full Text Available Current therapies for acute myeloid leukemia (AML, failing induction, are rarely effective. We report our experience in 4 patients with AML who received 16 Gy TBI prior to allogeneic hematopoietic cell transplantation (alloHCT, between June 2010 and May 2011. Patients were 20 to 55 years of age, 2 with relapsed disease and 2 with AML failing induction. An HLA-matched graft from related or unrelated donor was infused on day 0. All but one, who received a CD34+-selected graft, received methotrexate and tacrolimus +/− antithymocyte globulin, as GVHD prophylaxis. The other patient received tacrolimus alone. Neutrophil and platelet engraftment occurred at a median of 18 and 14 days, respectively. Patients were discharged at a median of 28 days. There were no unexpected toxicities in the first 30 days. One patient had cytomegalovirus (CMV viremia and anorexia, at two months. One patient had grade 2 acute GVHD of the skin. One patient developed chronic GVHD of the eyes, mouth, skin, joints, and lung at 4 months. Two patients died from relapse of their leukemia at days 65 and 125. Two patients remain in remission beyond day 1500. 16 Gy TBI followed by an alloHCT for AML, failing induction, is feasible and tolerable.

  20. [Characteristics and treatment outcomes in 822 adult patients with acute myeloid leukemia:a single center experience].

    Science.gov (United States)

    Lin, Dong; Zhou, Chunlin; Wei, Hui; Liu, Bingcheng; Wang, Ying; Liu, Kaiqi; Li, Wei; Gong, Benfa; Wang, Jinyu; Wei, Shuning; Zhang, Guangji; Zhao, Xingli; Li, Yan; Liu, Yuntao; Gong, Xiaoyuan; Sun, Mingyuan; Lu, Yuan; Mi, Yingchang; Wang, Jianxiang

    2014-12-01

    To investigate the characteristics and the short- or long-term treatment outcomes of the adult patients with acute myeloid leukemia (AML) in China. From 1999 to 2010, 822 adult cases with AML were enrolled, diagnosed and classified by the FAB and WHO criteria, respectively. The treatment outcomes and prognostic factors were analyzed retrospectively. In all patients with a median age of 38.5(15-83) years, acute monoblastic and monocytic leukemia (M5), AML with t(15;17)/PML-RARα (APL) and AML with t(8;21)/AML1-ETO(M2b) were the most common subtypes, accounting for 29.7%, 20.9% and 14.6% respectively. In APL patients, CR was achieved in 95.2%, with an early death (ED) rate of 4.8%. And the estimated overall survival (OS) and disease-free survival (DFS) at 5 year was 87.5% and 88.8%, respectively. Patients with other AML subtype (Non-APL) revealed a CR rate of 82.0%, ED of 4.3%, and estimated 5-year OS and DFS both of 48.8%. The OS rate of Non-APL patients at 3-year varied significantly (Pleukemia centers. Chemotherapy by risk stratification, after diagnosis and classification according to the WHO criteria, is a key point to improve the outcomes in AML.

  1. Prognostic value of IDH1 mutations identified with PCR-RFLP assay in acute myeloid leukemia patients

    International Nuclear Information System (INIS)

    Elsayed, Gh.M.; Zaher, A.; Elnoshokaty, E.H.; Nassar, H.R.; Moneer, M.M.

    2014-01-01

    Background: Somatic mutations in isocitrate dehydrogenase 1 (1DH1) gene occur frequently in primary brain tumors. Recently theses mutations were demonstrated in acute myeloid leukemia (AML). So far, assessment of these mutations relied on the DNA sequencing technique. Aim of the work: The aim of this study was to detect somatic mutations in IDH1 gene using mismatched primers suitable for endonuclease based detection, without the need for DNA sequencing, and to estimate its prognostic value, on patients with de novo AML. Methods: Residual DNA extracted from pretreatment bone marrow (BM) samples of 100 patients with de novo AML was used. The polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) was adapted to IDHl gene, codon 132 mutations screening. Results: The frequency of IDH1 mutations was 13%. In the non-acute promyelocytic leukemia group (non-APL), IDH1 mutations were significantly associated with FLT3-ITD negative patients (p = 0.03). Patients with 1DH1 mutations did not achieve complete remission (CR). There was a trend for shorter overall survival (OS) in patients with IDH1 mutation compared to those with wild type (p = 0.08). Conclusion: IDH1 mutations are recurring genetic alterations in AML and they may have unfavorable impact on clinical outcome in adult AML. The PCR-RFLP method allows for a fast, inexpensive, and sensitive method for the detection of IDF11 mutations in AML.

  2. In vivo and in vitro expression of myeloid antigens on B-lineage acute lymphoblastic leukemia cells.

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    Hara, J; Kawa-Ha, K; Yumura-Yagi, K; Kurahashi, H; Tawa, A; Ishihara, S; Inoue, M; Murayama, N; Okada, S

    1991-01-01

    The expression of myeloid antigens has been extensively examined using two-color analysis in 43 children with B-lineage acute lymphoblastic leukemia (ALL). On pre-culture cells, CD33 expression was frequently observed in CD19+, CD10- B-precursor ALL, and CD14 was expressed only on the cells from B-precursor ALL expressing CD19, CD10 and CD20, and B-ALL. After 2 or 3 days of culture without TPA, CD13 emerged on the cells from 21 of 29 patients irrespective of the presence or the absence of fetal calf serum in the culture. Of four patients with CD10+ B-precursor ALL, which showed no expression of CD13 after culture, two had T-cell associated antigens. Whereas the addition of TPA to the culture enhanced the expression of CD13 on the cells from acute non-lymphocytic leukemia (ANLL), TPA reduced the expression of this antigen on B-precursor cells. These findings suggest that the regulatory mechanism of CD13 expression may be different between B-precursor ALL and ANLL. Co-culture with cycloheximide mostly abrogated the induction of CD13, suggesting that CD13 expression was mainly dependent on de novo protein synthesis.

  3. Acute leukemias of ambiguous origin.

    Science.gov (United States)

    Porwit, Anna; Béné, Marie C

    2015-09-01

    This session of the Society for Hematopathology/European Association for Haematopathology Workshop focused on acute leukemias of ambiguous origin. We provide an overview of mixed-phenotype acute leukemia (MPAL) as recognized in the current World Health Organization classification and summarize diagnostic criteria for major categories of MPAL: B/myeloid, T/myeloid, B/T, and B/T/myeloid. Most MPAL cases submitted were B/myeloid and T/myeloid MPAL, the most frequent types, but three cases of B/T MPAL were also submitted, and examples of all categories are illustrated. We emphasize that a comprehensive approach to immunophenotyping is required to accurately establish the diagnosis of MPAL. Flow cytometry immunophenotyping using a large panel of antibodies is needed as well as confirmatory immunohistochemical analysis and cytochemistry studies for myeloperoxidase and nonspecific esterase. We discuss technical issues in determining blast lineage and possible pitfalls in MPAL diagnosis. In particular, rare cases of B-acute lymphoblastic leukemia (B-ALL) can express myeloperoxidase but are otherwise consistent with B-ALL and should be treated as such. Last, we review the differential diagnosis between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation. There was an agreement that diagnosis of MPAL can be challenging, especially if applied flow cytometry panels are not comprehensive enough. Copyright© by the American Society for Clinical Pathology.

  4. How I treat atypical chronic myeloid leukemia.

    Science.gov (United States)

    Gotlib, Jason

    2017-02-16

    Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited. © 2017 by The American Society of Hematology.

  5. MicroRNA-183 promotes cell proliferation via regulating programmed cell death 6 in pediatric acute myeloid leukemia.

    Science.gov (United States)

    Wang, Xiang; Zuo, Dongjian; Yuan, Yufang; Yang, Xiaochun; Hong, Ze; Zhang, Rongrong

    2017-01-01

    The aim of this study was to investigate roles of microRNA (miR)-183 in pediatric acute myeloid leukemia (AML). miR-183 expression in bone marrow and patients' sera of childhood AML was detected by real-time quantitative PCR. Functions of miR-183 in malignant phenotypes of two leukemia cell lines were then evaluated. Additionally, putative targets of miR-183 were predicted using three miRNA target prediction algorithms and validated by luciferase reporter assay. Clinical relevance of miR-183 and its target gene were further determined. miR-183 expression in bone marrow and patients' sera of childhood AML was both significantly higher than those in the corresponding normal controls (both P leukemia cells. Bioinformatics prediction and luciferase reporter assay identified programmed cell death 6 (PDCD6) as a direct target gene of miR-183. Moreover, high serum miR-183 combined with low serum PDCD6 mRNA was significantly associated with French-American-British classification subtype M7 (P = 0.01) and unfavorable karyotypes (P = 0.006). Further multivariate analysis identified the combination of serum miR-183 and PDCD6 levels as an independent prognostic factor for both relapse-free and overall survivals. Functionally, re-introduction of PDCD6 markedly reversed the effects of miR-183 in cell cycle, proliferation and apoptosis of two leukemia cell lines. Combined serum miR-183 and PDCD6 mRNA may serve as a novel prognostic biomarker for pediatric AML. Interestingly, miR-183 may function as an oncogene and may enhance cell proliferation by targeting PDCD6, implying a potential therapeutic target for this malignancy.

  6. Expression of the C- KIT Molecule in Acute Myeloid Leukemias: Implications of the Immuno phenotypes CD117 and CD15 in the Detection of Minimal Residual Disease

    International Nuclear Information System (INIS)

    Omar, S.

    2001-01-01

    Study of the c-kit proto-oncogene (CD117) may be of help for the identification of phenotypic profiles that are absent or present at very low frequencies on normal human blast cells and therefore might be of great value for the detection of leukemic cells displaying such immuno phenotypes in patients in complete remission. Design and methods: Ninety patients with acute myeloid leukemias, diagnosed according to FAB criteria and immunological marker studies, were studied for the dual expression on blast cells of the CD117/CD15 immuno phenotype co expression by direct immunofluorescence assay using dual staining combination flow cytometry. Results: In 69/90 acute myeloid leukemia patients analyzed (77%), blast cells expressed the CD117 antigen. Moreover, in 38 of them (42% of acute myeloid leukemia cases), leukemic blasts co expressed the CD117 and CD15 antigens. There was no significant correlation between the FAB classification and the CD117 and CD15 expression in acute myeloid leukemia cases. Conclusions: These results suggest that immunological methods for the detection of MRD based on the existence of aberrant phenotypes could be used in the majority of AML patients. This phenotype CD117/CD15, present in acute myeloid leukemia cases at a relatively high frequency (42%), represents an aberrant phenotype, because it was not detected on normal human blast cells, suggesting that the use of these combinations of monoclonal antibodies could be of help in detecting residual leukemic blasts among normal blast cells. The use of the CD117 antigen in different monoclonal antibodies combinations may be of great help for the detection of minimal residual disease in a high proportion of acute myeloid leukemia cases, especially in those patients displaying the CD117+/CD15+ immuno phenotype, because cells co expressing both antigens in normal blasts, if present, are at very low frequencies. The simultaneous assessment of two or more markers in single cells has facilitated the

  7. Re-evaluation of various molecular targets located on CD34+CD38-Lin-leukemia stem cells and other cell subsets in pediatric acute myeloid leukemia.

    Science.gov (United States)

    Cheng, Yuping; Jia, Ming; Chen, Yuanyuan; Zhao, Haizhao; Luo, Zebin; Tang, Yongmin

    2016-01-01

    Leukemia stem cells (LSCs) are hypothesized to be capable of driving the development of leukemia, and are responsible for disease relapse. Antibody therapy targeting cell surface antigens has significantly improved the treatment outcomes of leukemia. Therefore, it is important to identify cell surface markers that are expressed on LSCs, and that are unexpressed or expressed at reduced levels on normal hematopoietic stem cells (HSCs), in order to establish novel therapeutic targets. In the present study, the immunophenotypic characteristics of cluster of differentiation (CD)34 + CD38 - lineage (Lin) - stem cells were analyzed, and antigen expression levels were compared with the expression of other cell components, using multicolor flow cytometry, in 54 patients with newly diagnosed acute myeloid leukemia (AML) and 11 control patients with immune thrombocytopenia. The findings indicated that CD133 and human leukocyte antigen (HLA)-DR were expressed on normal HSCs and on AML LSCs, with no significant difference (P>0.05). By contrast, CD33, CD123 and CD44 were highly expressed on AML LSCs, and demonstrated significant differences compared with their expression on normal HSCs (CD33, 81.7 vs. 18.3%; CD123, 75.8 vs. 19.1%; CD44, 97.7 vs. 84.4%). Among the aforementioned antigens, CD33 and CD123 were promising candidates for targeted therapy for the treatment of AML. This was particularly evident for CD123 in immature AML subtype cells, which may require additional investigation within a clinical trial setting. CD44, CD133 and HLA-DR may not be suitable for leukemia targeting due to their broad and high expression levels on normal HSCs and other tissues.

  8. Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia

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    Matteo G. Carrabba

    2016-10-01

    Full Text Available Abstract Despite the considerable progress in understanding the molecular bases of acute myeloid leukemia (AML, new tools to link disease biology to the unpredictable patient clinical course are still needed. Herein, high-throughput metabolomics, combined with the other “-omics” disciplines, holds promise in identifying disease-specific and clinically relevant features. In this study, we took advantage of nuclear magnetic resonance (NMR to trace AML-associated metabolic trajectory employing two complementary strategies. On the one hand, we performed a prospective observational clinical trial to identify metabolic changes associated with blast clearance during the first two cycles of intensive chemotherapy in nine adult patients. On the other hand, to reduce the intrinsic variability associated with human samples and AML genetic heterogeneity, we analyzed the metabolic changes in the plasma of immunocompromised mice upon engraftment of primary human AML blasts. Combining the two longitudinal approaches, we narrowed our screen to seven common metabolites, for which we observed a mirror-like trajectory in mice and humans, tracing AML progression and remission, respectively. We interpreted this set of metabolites as a dynamic fingerprint of AML evolution. Overall, these NMR-based metabolomic data, to be consolidated in larger cohorts and integrated in more comprehensive system biology approaches, hold promise for providing valuable and non-redundant information on the systemic effects of leukemia.

  9. MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia.

    Science.gov (United States)

    Verboon, Lonneke J; Obulkasim, Askar; de Rooij, Jasmijn D E; Katsman-Kuipers, Jenny E; Sonneveld, Edwin; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Pieters, Rob; Cloos, Jacqueline; Kaspers, Gertjan J L; Klusmann, Jan-Henning; Zwaan, Christian Michel; Fornerod, Maarten; van den Heuvel-Eibrink, Marry M

    2016-07-26

    The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements.

  10. High resolution melting curve analysis, a rapid and affordable method for mutation analysis in childhood acute myeloid leukemia

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    Yin eLiu

    2014-09-01

    Full Text Available Background: Molecular genetic alterations with prognostic significance have been described in childhood acute myeloid leukemia (AML. The aim of this study was to establish cost-effective techniques to detect mutations of FMS-like tyrosine kinase 3 (FLT3, Nucleophosmin 1 (NPM1, and a partial tandem duplication within the mixed lineage leukemia (MLL-PTD genes in childhood AML. Procedure: Ninety-nine children with newly diagnosed AML were included in this study. We developed a fluoresent dye SYTO-82 based high resolution melting curve (HRM anaylsis to detect FLT3 internal tandem duplication (FLT3-ITD, FLT3 tyrosine kinase domain (FLT3-TKD and NPM1 mutations. MLL-PTD was screened by real-time quantitative PCR. Results: The HRM methodology correlated well with gold standard Sanger sequencing with less cost. Among the 99 patients studied, the FLT3-ITD mutation was associated with significantly worse event free survival (EFS. Patients with the NPM1 mutation had significantly better EFS and overall survival. However, HRM was not sensitive enough for minimal residual disease monitoring. Conclusions: HRM was a rapid and efficient method for screening of FLT3 and NPM1 gene mutations. It was both affordable and accurate, especially in resource underprivileged regions. Our results indicated that HRM could be a useful clinical tool for rapid and cost effective screening of the FLT3 and NPM1 mutations in AML patients.

  11. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia.

    Science.gov (United States)

    Keeton, Erika K; McEachern, Kristen; Dillman, Keith S; Palakurthi, Sangeetha; Cao, Yichen; Grondine, Michael R; Kaur, Surinder; Wang, Suping; Chen, Yuching; Wu, Allan; Shen, Minhui; Gibbons, Francis D; Lamb, Michelle L; Zheng, Xiaolan; Stone, Richard M; Deangelo, Daniel J; Platanias, Leonidas C; Dakin, Les A; Chen, Huawei; Lyne, Paul D; Huszar, Dennis

    2014-02-06

    Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.

  12. Diagnóstico laboratorial das leucemias mielóides agudas Laboratory diagnosis of acute myeloid leukemias

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    Graziele C. da Silva

    2006-04-01

    Full Text Available As leucemias agudas caracterizam-se pela proliferação clonal e pelo bloqueio maturativo das células hematopoéticas, com substituição difusa da medula óssea por células neoplásicas. A leucemia mielóide aguda (LMA é um grupo heterogêneo de doenças clonais do tecido hematopoético, que acomete predominantemente idosos acima de 60 anos de idade. A LMA apresenta oito subtipos distintos morfologicamente: LMA M0 a M7. Os métodos diagnósticos para identificação da LMA e classificação dos subtipos são baseados em critérios morfológicos, citoquímicos e de imunofenotipagem, acrescidos de análise genética. Além de ser importante para a diferenciação do tipo da linhagem da leucemia, se mielóide (LMA ou linfóide (LLA, o diagnóstico é também de grande importância para identificar a leucemia bifenotípica aguda (BAL. O objetivo deste trabalho foi realizar uma revisão bibliográfica sobre LMA, dando ênfase aos métodos laboratoriais utilizados para a sua identificação e diferenciação.The acute leukemias are characterized by the clonal proliferation and maturative blockage of hematopoietic cells, with diffuse substitution of the bone marrow by neoplasic cells. The acute myeloid leukemia (AML is a heterogeneous group of clonal disease in the hematopoietic tissue and predominantly affects people older than 60. The AML has eight morphologically different subtypes: AML M0 to M7. The diagnostic methods for identification of AML and subtypes classification are based on morphological, cytochemical and immunophenotyping patterns, besides genetic and molecular analyses. The diagnosis of leukemia is important to the lineage differentiation in AML or ALL and also for the identification of biphenotypic acute leukemia (BAL. The aim of this study was to perform a bibliographic review of AML, giving emphasis on laboratory methods useful for its identification and differentiation.

  13. POU1F1 is a novel fusion partner of NUP98 in acute myeloid leukemia with t(3;11)(p11;p15).

    Science.gov (United States)

    Lisboa, Susana; Cerveira, Nuno; Bizarro, Susana; Correia, Cecília; Vieira, Joana; Torres, Lurdes; Mariz, José M; Teixeira, Manuel R

    2013-01-18

    NUP98 gene rearrangements have been reported in acute myeloid leukemia, giving rise to fusion proteins that seem to function as aberrant transcription factors, and are thought to be associated with poor prognosis. A patient with treatment-related acute myeloid leukemia presented a t(3;11)(p11;p15) as the only cytogenetic abnormality. FISH and molecular genetic analyses identified a class 1 homeobox gene, POU1F1, located on chromosome 3p11, as the fusion partner of NUP98. In addition, we have found that the patient harbored an FLT3-ITD mutation, which most likely collaborated with the NUP98-POU1F1 fusion gene in malignant transformation. We have identified POU1F1 as the NUP98 fusion partner in therapy-related AML with a t(3;11)(p11;p15). This is the first POU family member identified as a fusion partner in human cancer.

  14. Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93.

    Science.gov (United States)

    Creutzig, U; Ritter, J; Zimmermann, M; Reinhardt, D; Hermann, J; Berthold, F; Henze, G; Jürgens, H; Kabisch, H; Havers, W; Reiter, A; Kluba, U; Niggli, F; Gadner, H

    2001-05-15

    To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) 87. Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P =.01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P =.007; and 44% v 31%, P =.01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.

  15. Acute myeloid leukemia-targeted toxin activates both apoptotic and necroptotic death mechanisms.

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    Henrick Horita

    Full Text Available BACKGROUND: Acute myelogenous leukemia (AML is the second most common leukemia with approximately 13,410 new cases and 8,990 deaths annually in the United States. A novel fusion toxin treatment, diphtheria toxin GM-CSF (DT-GMCSF has been shown to selectively eliminate leukemic repopulating cells that are critical for the formation of AML. We previously showed that DT-GMCSF treatment of U937 cells, an AML cell line, causes activation of caspases and the induction of apoptosis. METHODS AND FINDINGS: In this study we further investigate the mechanisms of cell death induced by DT-GMCSF and show that, in addition to the activation of caspase-dependent apoptosis, DT-GMCSF also kills AML cells by simultaneously activating caspase-independent necroptosis. These mechanisms depend on the ability of the targeted toxin to inhibit protein synthesis, and are not affected by the receptor that is targeted or the mechanism through which protein synthesis is blocked. CONCLUSIONS: We conclude that fusion toxin proteins may be effective for treating AML cells whether or not they are defective in apoptosis.

  16. MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias

    International Nuclear Information System (INIS)

    Spinello, I; Quaranta, M T; Riccioni, R; Riti, V; Pasquini, L; Boe, A; Pelosi, E; Vitale, A; Foà, R; Testa, U; Labbaye, C

    2011-01-01

    CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-leukemia drugs, for development of new therapeutic strategies

  17. Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group.

    Science.gov (United States)

    Gröschel, Stefan; Schlenk, Richard F; Engelmann, Jan; Rockova, Veronika; Teleanu, Veronica; Kühn, Michael W M; Eiwen, Karina; Erpelinck, Claudia; Havermans, Marije; Lübbert, Michael; Germing, Ulrich; Schmidt-Wolf, Ingo G H; Beverloo, H Berna; Schuurhuis, Gerrit J; Ossenkoppele, Gert J; Schlegelberger, Brigitte; Verdonck, Leo F; Vellenga, Edo; Verhoef, Gregor; Vandenberghe, Peter; Pabst, Thomas; Bargetzi, Mario; Krauter, Jürgen; Ganser, Arnold; Valk, Peter J M; Löwenberg, Bob; Döhner, Konstanze; Döhner, Hartmut; Delwel, Ruud

    2013-01-01

    To evaluate the prognostic value of ecotropic viral integration 1 gene (EVI1) overexpression in acute myeloid leukemia (AML) with MLL gene rearrangements. We identified 286 patients with AML with t(11q23) enrolled onto German-Austrian Acute Myeloid Leukemia Study Group and Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group prospective treatment trials. Material was available from 177 AML patients for EVI1 expression analysis. We divided 286 MLL-rearranged AMLs into three subgroups: t(9;11)(p22;q23) (44.8%), t(6;11)(q27;q23) (14.7%), and t(v;11q23) (40.5%). EVI1 overexpression (EVI1(+)) was found in 45.8% of all patients with t(11q23), with t(6;11) showing the highest frequency (83.9%), followed by t(9;11) at 40.0%, and t(v;11q23) at 34.8%. Concurrent gene mutations were rare or absent in all three subgroups. Within all t(11q23) AMLs, EVI1(+) was the sole prognostic factor, predicting for inferior overall survival (OS; hazard ratio [HR], 2.06; P = .003), relapse-free survival (HR, 2.28; P = .002), and event-free survival (HR, 1.79; P = .009). EVI1(+) AMLs with t(11q23) in first complete remission (CR) had a significantly better outcome after allogeneic transplantation compared with other consolidation therapies (5-year OS, 54.7% v 0%; Mantel-Byar, P = .0006). EVI1(-) t(9;11) AMLs had lower WBC counts, more commonly FAB M5 morphology, and frequently had additional trisomy 8 (39.6%; P < .001). Among t(9;11) AMLs, EVI1(+) again was the sole independent adverse prognostic factor for survival. Deregulated EVI1 expression defines poor prognostic subsets among AML with t(11q23) and AML with t(9;11)(p22;q23). Patients with EVI1(+) MLL-rearranged AML seem to benefit from allogeneic transplantation in first CR.

  18. Chemopreventive Potential of Major Flavonoid Compound of Methanolic Bark Extract of Saraca asoca (Roxb.) in Benzene-induced Toxicity of Acute Myeloid Leukemia Mice

    OpenAIRE

    Mukhopadhyay, Manas Kumar; Shaw, Mithun; Nath, Debjani

    2017-01-01

    Background: Saraca asoca (SA) (Roxb.) is one of the folk medicinal plants found in India, Bangladesh, and Sri Lanka. Its major biological activity appears due to the presence of flavonoid group of compounds in its bark extract. Objective: In this study, our research aims to analyze the chemopreventive effect of flavonoids, especially a natural phenol catechin present in the bark methanolic extract of SA on acute myeloid leukemia (AML) mice. Materials and Methods: The total bark extract was pa...

  19. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions | Office of Cancer Genomics

    Science.gov (United States)

    We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children’s Oncology Group (COG) AML trials. The COG–National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases.

  20. Rapid Assessment of the Heterogeneous Methylation Status of CEBPA in Patients with Acute Myeloid Leukemia by Using High-Resolution Melting Profile

    OpenAIRE

    Lin, Tsung-Chin; Jiang, Sin-Sien; Chou, Wen-Chien; Hou, Hsin-An; Lin, Yu-Min; Chang, Chia-Ling; Hsu, Cherng-An; Tien, Hwei-Fang; Lin, Liang-In

    2011-01-01

    Epigenetic inactivation of tumor-suppressor genes, often in association with aberrant DNA methylation of CpG islands in the promoter region of these genes, is a key factor in tumorigenesis. CCAAT/enhancer binding protein alpha (CEBPA) methylation is a favorable prognostic biomarker for acute myeloid leukemia; however, rather than the complete methylation observed in inherited disorders, CEBPA methylation is heterogeneous. In this study, we established an algorithm called the “methylation inde...

  1. HLA-DR(negative), CD34(negative) hypergranular acute myeloid leukemia with trisomy 6 and del(5)(q22q33): case report and review of the literature.

    Science.gov (United States)

    Argiropoulos, Bob; Clifford, Brian; Crocker, Susan; Sinclair-Bourque, Elizabeth; McCready, Elizabeth; McGowan-Jordan, Jean; Johnston, Donna L; Padmore, Ruth

    2011-10-01

    We report a unique pediatric case of hypergranular acute myeloid leukemia with myelodysplasia-related changes. The patient presented with moderate leukocytosis with neutrophilia with left-shift maturation and dysplasia, anemia, and multiple sclerotic bone lesions. The bone marrow was hypercellular with a predominance of myeloblast cells and/or abnormal promyelocytes with hypergranular cytoplasm. Flow cytometric immunophenotyping showed that the leukemic cells were positive for CD13, CD33, and myeloperoxidase, and negative for HLA-DR and CD34. Morphology and immunophenotyping were highly suggestive of acute promyelocytic leukemia. The classic t(15;17) or other RARα rearrangements were not detected by cytogenetic or molecular assays, ruling out acute promyelocytic leukemia. Standard cytogenetic analysis showed that the karyotype of the predominant clone was 47,XY,+6 with evidence of clonal evolution to 47,XY,+6,del(5)(q22q33). A literature and database review showed that trisomy 6 is a rare occurrence in hematological malignancies and, to our knowledge, has never been reported in association with del(5)(q22q33) in a child presenting with hypergranular acute myeloid leukemia with myelodysplasia-related changes. We present a current review of the literature and summarize the clinical features of 57 cases of trisomy 6 as the primary chromosomal abnormality in hematological disease.

  2. Acute Myeloid Leukemia and Myelodysplastic Syndromes After Radiation Therapy Are Similar to De Novo Disease and Differ From Other Therapy-Related Myeloid Neoplasms

    Science.gov (United States)

    Nardi, Valentina; Winkfield, Karen M.; Ok, Chi Young; Niemierko, Andrzej; Kluk, Michael J.; Attar, Eyal C.; Garcia-Manero, Guillermo; Wang, Sa A.; Hasserjian, Robert P.

    2012-01-01

    Purpose Therapy-related myeloid neoplasms (t-MN) represent a unique clinical syndrome occurring in patients treated with chemotherapy and/or external-beam radiation (XRT) and are characterized by poorer prognosis compared with de novo disease. XRT techniques have evolved in recent years and are associated with significantly reduced bone marrow exposure. The characteristics of post-XRT t-MN in the current era have not been studied. Patients and Methods We analyzed patients who developed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after XRT alone (47 patients) or cytotoxic chemotherapy/combined-modality therapy (C/CMT, 181 patients) and compared them with patients with de novo MDS or AML (222 patients). We estimated bone marrow exposure to radiation and compared the clinical, pathologic, and cytogenetic features and outcome of the XRT patients with the C/CMT patients and with patients with de novo MDS and AML. Results Patients with t-MN after XRT alone had superior overall survival (P = .006) and lower incidence of high-risk karyotypes (P = .01 for AML and < .001 for MDS) compared with patients in the C/CMT group. In contrast, there were no significant differences in survival or frequency of high-risk karyotypes between the XRT and de novo groups. Conclusion AML and MDS diagnosed in the past decade in patients after receiving XRT alone differ from t-MN occurring after C/CMT and share genetic features and clinical behavior with de novo AML/MDS. Our results suggest that post-XRT MDS/AML may not represent a direct consequence of radiation toxicity and warrant a therapeutic approach similar to de novo disease. PMID:22585703

  3. The co-presence of deletion 7q, 20q and inversion 16 in therapy-related acute myeloid leukemia developed secondary to treatment of breast cancer with cyclophosphamide, doxorubicin, and radiotherapy: a case report

    Directory of Open Access Journals (Sweden)

    Yonal Ipek

    2012-02-01

    Full Text Available Abstract Introduction Therapy-related acute myeloid leukemia occurs as a complication of treatment with chemotherapy, radiotherapy, immunosuppressive agents or exposure to environmental carcinogens. Case presentation We report a case of therapy-related acute myeloid leukemia in a 37-year-old Turkish woman in complete remission from breast cancer. Our patient presented to our facility with fatigue, fever, sore throat, peripheral lymphadenopathy, and moderate hepatosplenomegaly. On peripheral blood and bone marrow aspirate smears, monoblasts were present. Immunophenotypic analysis of the bone marrow showed expression of CD11b, CD13, CD14, CD15, CD33, CD34, CD45 and human leukocyte antigen-DR, findings compatible with the diagnosis of acute monoblastic leukemia (French-American-British classification M5a. Therapy-related acute myeloid leukemia developed three years after adjuvant chemotherapy consisting of an alkylating agent, cyclophosphamide and DNA topoisomerase II inhibitor, doxorubicin and adjuvant radiotherapy. Cytogenetic analysis revealed a 46, XX, deletion 7 (q22q34, deletion 20 (q11.2q13.1 karyotype in five out of 20 metaphases and inversion 16 was detected by fluorescence in situhybridization. There was no response to chemotherapy (cytarabine and idarubicin, FLAG-IDA protocol, azacitidine and our patient died in the 11th month after diagnosis. Conclusions The median survival in therapy-related acute myeloid leukemia is shorter compared to de novoacute myeloid leukemia. Also, the response to therapy is poor. In therapy-related acute myeloid leukemia, complex karyotypes have been associated with abnormalities of chromosome 5, rather than 7. To the best of our knowledge, this is the first case of therapy-related acute myeloid leukemia showing the co-presence of deletion 7q, 20q and the inversion 16 signal.

  4. Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases.

    Science.gov (United States)

    Michels, S D; McKenna, R W; Arthur, D C; Brunning, R D

    1985-06-01

    This study consists of 65 patients (pts) who developed a myelodysplastic syndrome (MDS) (39 pts) or acute myeloid leukemia (AML) (26 pts) following chemotherapy and/or radiotherapy; the interval from the onset of therapy to bone marrow abnormality ranged from 11 to 192 months (median, 58). Thirty-three patients had been previously treated for lymphoproliferative diseases, 29 for carcinoma, and three for a nonneoplastic disorder. Approximately 30% of the cases presenting in the MDS phase evolved to AML in one to 12 months (median, 3.5). The AML in 49% of the cases was not readily classified according to French-American-British (FAB) criteria; the primary difficulty in classification related to the involvement of multiple cell lines. Among the cases that could be classified, all FAB types were represented except for M1; M2 was the most frequent type. Clonal chromosome abnormalities were found in marrow specimens from 22 of 24 (92%) patients studied with G banding; 11 had abnormalities of chromosomes 5 and/or 7. The median survival for all patients was four months with no significant difference between those treated and not treated with antileukemic therapy. The median survival was three months for the patients presenting with AML, six months for the patients with AML following an MDS, and four months for the patients with an MDS that did not evolve to AML. The findings in the present study suggest that there are three stages of therapy-related panmyelosis: (1) pancytopenia with associated myelodysplastic changes, (2) a frank MDS, and (3) overt AML. Many patients will present in the stage of overt AML that differs from de novo AML primarily by the high incidence of trilineage involvement, difficulty in classification, frequent cytogenetic abnormalities, and poor response to antileukemic therapy. The myelodysplastic phase, with or without evolution to acute leukemia, is a highly lethal disease with a median survival comparable to that of the patients who present with

  5. Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene.

    Science.gov (United States)

    Masetti, Riccardo; Bertuccio, Salvatore Nicola; Astolfi, Annalisa; Chiarini, Francesca; Lonetti, Annalisa; Indio, Valentina; De Luca, Matilde; Bandini, Jessica; Serravalle, Salvatore; Franzoni, Monica; Pigazzi, Martina; Martelli, Alberto Maria; Basso, Giuseppe; Locatelli, Franco; Pession, Andrea

    2017-01-21

    CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.

  6. Leukemia-associated aberrant immunophenotype in patients with acute myeloid leukemia: changes at refractory disease or first relapse and clinicopathological findings.

    Science.gov (United States)

    Cui, W; Zhang, D; Cunningham, M T; Tilzer, L

    2014-12-01

    Multiparameter flow cytometry (MFC) is commonly used to detect minimal residual disease (MRD) during the course of chemotherapy or relapse. Only one study addressed the immunophenotypic changes in refractory disease. We studied changes in leukemia-associated aberrant immunophenotype (LAIP) in patients with refractory and relapsed acute myeloid leukemia (AML). We analyzed 47 patients (refractory = 22; relapsed = 25) by MFC, morphology, and cytogenetic studies. Thirty-five patients (74%) showed variably changed LAIPs. The frequently altered LAIPs were lack of lineage-specific antigen and lineage infidelity. The most frequently changed marker was CD13, followed by CD33, CD56, CD7, CD4, and CD11b. Cytogenetic clonal evolution at persistence/relapse was observed in 15 patients (32%). Morphologically, three patients (6%) showed significant changes at relapse. Patients with refractory AML had a higher association with poor cytogenetic risk and classification of AML with myelodysplasia-related changes. Positive MRD at postinduction was of prognostic significance. Allogeneic stem cell transplant improved overall survival. LAIP alterations in refractory/relapsed AMLs are common findings. Presence of persistent disease indicates a poor prognosis, regardless of cytogenetic risk or expression of CD7 or CD56. Discordance between cytogenetic and LAIP changes suggests that gross cytogenetic clonal evolution during disease progression only partly contributes to immunophenotypic instability. © 2014 John Wiley & Sons Ltd.

  7. Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503).

    Science.gov (United States)

    Blum, W; Sanford, B L; Klisovic, R; DeAngelo, D J; Uy, G; Powell, B L; Stock, W; Baer, M R; Kolitz, J E; Wang, E S; Hoke, E; Mrózek, K; Kohlschmidt, J; Bloomfield, C D; Geyer, S; Marcucci, G; Stone, R M; Larson, R A

    2017-01-01

    In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m 2 intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.

  8. Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells

    DEFF Research Database (Denmark)

    Agger, Karl; Miyagi, Satoru; Pedersen, Marianne Terndrup

    2016-01-01

    Acute myeloid leukemias (AMLs) with a rearrangement of the mixed-linage leukemia (MLL) gene are aggressive hematopoietic malignancies. Here, we explored the feasibility of using the H3K9- and H3K36-specific demethylases Jmjd2/Kdm4 as putative drug targets in MLL-AF9 translocated leukemia. Using...... a mechanism involving removal of H3K9me3 from the promoter of the Il3ra gene. Importantly, ectopic expression of Il3ra in Jmjd2/Kdm4 knockout cells alleviates the requirement of Jmjd2/Kdm4 for the survival of AML cells, showing that Il3ra is a critical downstream target of Jmjd2/Kdm4 in leukemia...

  9. Connect MDS/AML: design of the myelodysplastic syndromes and acute myeloid leukemia disease registry, a prospective observational cohort study.

    Science.gov (United States)

    Steensma, David P; Abedi, Medrdad; Bejar, Rafael; Cogle, Christopher R; Foucar, Kathryn; Garcia-Manero, Guillermo; George, Tracy I; Grinblatt, David; Komrokji, Rami; Ma, Xiaomei; Maciejewski, Jaroslaw; Pollyea, Daniel A; Savona, Michael R; Scott, Bart; Sekeres, Mikkael A; Thompson, Michael A; Swern, Arlene S; Nifenecker, Melissa; Sugrue, Mary M; Erba, Harry

    2016-08-19

    Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid neoplasms in which outgrowth of neoplastic clones disrupts normal hematopoiesis. Some patients with unexplained persistent cytopenias may not meet minimal diagnostic criteria for MDS but an alternate diagnosis is not apparent; the term idiopathic cytopenia of undetermined significance (ICUS) has been used to describe this state. MDS and AML occur primarily in older patients who are often treated outside the clinical trial setting. Consequently, our understanding of the patterns of diagnostic evaluation, management, and outcomes of these patients is limited. Furthermore, there are few natural history studies of ICUS. To better understand how patients who have MDS, ICUS, or AML are managed in the routine clinical setting, the Connect MDS/AML Disease Registry, a multicenter, prospective, observational cohort study of patients newly diagnosed with these conditions has been initiated. The Connect MDS/AML Disease Registry will capture diagnosis, risk assessment, treatment, and outcomes data for approximately 1500 newly diagnosed patients from approximately 150 community and academic sites in the United States in 4 cohorts: (1) lower-risk MDS (International Prognostic Scoring System [IPSS] low and intermediate-1 risk), with and without del(5q); (2) higher-risk MDS (IPSS intermediate-2 and high risk); (3) ICUS; and (4) AML in patients aged ≥ 55 years (excluding acute promyelocytic leukemia). Diagnosis will be confirmed by central review. Baseline patient characteristics, diagnostic patterns, treatment patterns, clinical outcomes, health economics outcomes, and patient-reported health-related quality of life will be entered into an electronic data capture system at enrollment and quarterly for 8 years. A tissue substudy to explore the relationship between karyotypes, molecular markers, and clinical outcomes will be conducted, and is optional for patients. The Connect MDS/AML Disease

  10. Method of automating of the separation of blasts and lymphocytes in the diagnosis of acute myeloid leukemia

    Science.gov (United States)

    Blindar, V. N.; Nikitaev, V. G.; Polyakov, E. V.; Matveeva, I. I.

    2017-01-01

    The work deals with the separation of the lymphocytes of healthy patients from blasts of patients with acute myeloblastic leukemia (different variants of the disease). In this study the evaluation of textural characteristics has been done for nuclei of blood cells for cells classification and for the determination of a variant of acute myeloblastic leukemia.

  11. Marked response to imatinib mesylate in a patient with platelet-derived growth factor receptor beta-associated acute myeloid leukemia.

    Science.gov (United States)

    Shimomura, Yoshimitsu; Maruoka, Hayato; Ishikawa, Takayuki

    2017-05-01

    Abnormal platelet-derived growth factor receptor (PDGFR)-mediated signaling may cause hematologic neoplasm. The PDGFR beta (PDGFRB) gene, located at chromosome band 5q31-33, forms a fusion gene as a result of chromosome translocation. Although patients with PDGFRB rearrangement mostly present with myeloproliferative neoplasm and eosinophilia, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) have also been reported in this population. Treatment with imatinib mesylate alone has been shown to have excellent long-term efficacy against myeloproliferative neoplasms; however, its long-term effects on ALL and AML have not been elucidated. A 75-year-old man was diagnosed with acute myeloid leukemia having the PDGFRB and cGMP-dependent protein kinase 2 fusion gene with additional genetic abnormalities. Continuous therapy with single-agent imatinib mesylate resulted in cytogenetic remission and decreased molecular burden for 9 months; however, the leukemia subsequently recurred, and the patient died 1 year after initiation of treatment. This case report supports the importance of cytogenetic analysis during patient screening.

  12. Tailored central nervous system-directed treatment strategy for isolated CNS recurrence of adult acute myeloid leukemia.

    Science.gov (United States)

    Zheng, Changcheng; Liu, Xin; Zhu, Weibo; Cai, Xiaoyan; Wu, Jingsheng; Sun, Zimin

    2014-06-01

    The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML). Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation. The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6∼60.8 × 10(9)/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 × 10(9)/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P < 0.001, 0.005). Twenty-four out of 34 patients (70.6%) with CNS recurrence achieved CNS complete remission at a median of 58 days (range, 30-120). The 3-year disease-free survival and overall survival estimates for all CNS recurrence patients were 21.6 and 25.3%, respectively. This report indicates that the tailored CNS-directed strategy is an effective modality to treat CNS recurrence in adult AML, but further studies are needed to improve the long-term survival.

  13. CD7 in acute myeloid leukemia: correlation with loss of wild-type CEBPA, consequence of epigenetic regulation

    Directory of Open Access Journals (Sweden)

    Drexler Hans G

    2010-04-01

    Full Text Available Abstract Background CD7 is a negative prognostic marker in myeloid malignancies. In acute myeloid leukemia (AML, an inverse correlation exists between expression of wild-type CEBPA and CD7. Aim of this study was to find out whether C/EBPα is a negative regulator of CD7 and which other regulatory mechanisms might be involved. Results As already described for primary AML cells, the majority of AML cell lines tested were either C/EBPα+/CD7- or C/EBPα-/CD7+. However, the existence of isolated CD7+ cell lines expressing wild-type C/EBPα challenges the notion that C/EBPα acts as a unique repressor of CD7. Furthermore, ectopic expression of CEBPA did not reduce CD7 in CD7+ cells and knock-down of C/EBPα failed to induce CD7 in CD7- cells. In contrast, the DNA demethylating agent Aza-2'deoxycytidine triggered CD7 expression in CD7- AML and in T-cell lines suggesting epigenetic regulation of CD7. Bisulfite sequencing data confirmed that CpGs in the CD7 exon1 region are methylated in CD7- cell lines, and unmethylated in CD7+ cell lines. Conclusion We confirmed an inverse correlation between the expression of wild-type CEBPA and of CD7 in AML cells. Our results contradict the hypothesis that C/EBPα acts as repressor for CD7, and instead show that epigenetic mechanisms are responsible for CD7 regulation, in AML cells as well as in T-cells, the typical CD7 expressing cell type.

  14. FLT3 Mutation as a Significant Prognostic Marker in de novo Acute Myeloid Leukemia Patients: Incidence, Distribution and Association with Cytogenetic Findings in a Study from South India

    Directory of Open Access Journals (Sweden)

    Santhi Sarojam

    2014-10-01

    Full Text Available Background: Fms-like tyrosine kinase 3 is a tyrosine kinase receptor that plays an important role in proliferation and differentiation of hematopoietic stem cells. Internal tandem duplication and tyrosine kinase domain mutation are the two most common types of fms-like tyrosine kinase 3 mutations frequently reported in acute myeloid leukemia associated with pathogenesis of this disease. The present study investigates the prevalence and distribution pattern in different acute myeloid leukemia sub- and cytogenetic groups, the association with clinical parameters and the prognostic importance of these mutations in acute myeloid leukemia patients from South India. Methods:Mutation analysis was performed in 276 de novo acute myeloid leukemia patients by polymerase chain reaction restriction fragment length polymorphism using specific restriction enzymes followed by sequencing to confirm the mutations. Kaplan-Meier survival analysis was performed to detect the prognosis. Results: Fms-like tyrosine kinase 3 internal tandem duplication mutations were observed in 20%, tyrosine kinase domain mutation in 4% and dual mutations in 0.3% of the analyzed cases. The internal tandem duplication mutations ranged from 15-107 nucleotides with the majority at the juxta membrane domain of the receptor. Three types of tyrosine kinase domain point mutations were identified: D835Y, D835H and D835V. We observed a significant association between fms-like tyrosine kinase 3 mutations and increased WBC and LDH counts (P<0.001 and blast percentage but not with age, gender and FAB subtypes. A significant association with normal karyotype was observed for the mutants (P=0.002. Survival analysis revealed that the fms-like tyrosine kinase 3 gene mutation was a negative prognostic marker for acute myeloid leukemia patients. The risk stratified analysis showed the mutation to be a risk factor for the intermediate karyotype group, especially for those with normal cytogenetics

  15. Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia

    Science.gov (United States)

    Goardon, Nicolas; Morrison, Heather; Hamblin, Mike; Robinson, Lisa; Clark, Richard E.

    2016-01-01

    Chronic myeloid leukemia (CML) is an excellent model of the multistep processes in cancer. Initiating BCR-ABL mutations are required for the initial phase of the disease (chronic phase, CP-CML). Some CP-CML patients acquire additional mutation(s) that transforms CP-CML to poor prognosis, hard to treat, acute myeloid or lymphoid leukemia or blast phase CML (BP-CML). It is unclear where in the hemopoietic hierarchy additional mutations are acquired in BP-CML, how the hemopoietic hierarchy is altered as a consequence, and the cellular identity of the resulting leukemia-propagating stem cell (LSC) populations. Here, we show that myeloid BP-CML is associated with expanded populations that have the immunophenotype of normal progenitor populations that vary between patients. Serial transplantation in immunodeficient mice demonstrated functional LSCs reside in multiple populations with the immunophenotype of normal progenitor as well as stem cells. Multicolor fluorescence in situ hybridization detected serial acquisition of cytogenetic abnormalities of chromosome 17, associated with transformation to BP-CML, that is detected with equal frequency in all functional LSC compartments. New effective myeloid BP-CML therapies will likely have to target all these LSC populations. PMID:29296933

  16. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial.

    NARCIS (Netherlands)

    Suciu, S.; Mandelli, F.; Witte, T.J.M. de; Zittoun, R.; Gallo, E.; Labar, B.; Rosa, G. De; Belhabri, A.; Giustolisi, R.; Delarue, R.; Liso, V.; Mirto, S.; Leone, G.; Bourhis, J.; Fioritoni, G.; Jehn, U.; Amadori, S.; Fazi, P.; Hagemeijer, A.; Willemze, R.

    2003-01-01

    In the European Organization for Research and Treatment of Cancer Leukemia Group and Gruppo Italiano Malattie Ematologiche dell' Adulto (EORTC-LG/GIMEMA) acute myeloid leukemia (AML)-10 trial, patients in first complete remission (CR1) received a single intensive consolidation (IC) course.

  17. Involvement of BAFF and APRIL in Resistance to Apoptosis of Acute Myeloid Leukemia.

    Science.gov (United States)

    Bolkun, Lukasz; Grubczak, Kamil; Schneider, Gabriela; Zembko, Paula; Radzikowska, Urszula; Singh, Paulina; Kloczko, Janusz; Ratajczak, Mariusz Z; Moniuszko, Marcin; Eljaszewicz, Andrzej

    2016-01-01

    B-cell activation factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), two members of the tumour necrosis factor (TNF) superfamily, beyond playing a significant role in normal B-cell development, promote survival and proliferation of malignant B cells. Both ligands interact with 3 receptors: BAFF-R, specific to BAFF, and TACI and BCMA which are shared by both BAFF and APRIL. Here we wished to investigate the potential role of these proteins in resistance of acute myeloid leukaemia (AML) blasts to apoptosis. We found that the levels of both mRNA and proteins of APRIL, BAFF and their receptors were expressed in leukaemic cells of 24 newly diagnosed, untreated AML patients. We also demonstrated that patients who did not further respond to induction therapy (NR) presented with significantly higher baseline APRIL and BAFF expression on AML blasts as compared to these subjects who, after induction, achieved complete remission (CR) following induction therapy. Moreover, we observed striking differences in baseline levels of BCMA between CR and NR patients as we did not find detectable expression of this receptor in the latter group of patients. Interestingly, we found that AML blasts collected at baseline from NR patients cultured in presence of exogenous BAFF and APRIL were significantly more resistant to spontaneous or drug-induced apoptosis as compared with cells derived from CR patients. Altogether, our data confirm that BAFF and APRIL signaling play important role in AML pathogenesis and susceptibility to cytotoxic therapy while measuring of BCMA expression on AML cells can become a novel prognostic factor for chemotherapy response.

  18. Familial Myelodysplastic/Acute Leukemia Syndromes—Myeloid Neoplasms with Germline Predisposition

    Directory of Open Access Journals (Sweden)

    Renata Lyrio Rafael Baptista

    2017-09-01

    Full Text Available Although most cases of myeloid neoplasms are sporadic, a small subset has been associated with germline mutations. The 2016 revision of the World Health Organization classification included these cases in a myeloid neoplasm group with a predisposing germline mutational background. These patients must have a different management and their families should get genetic counseling. Cases identification and outline of the major known syndromes characteristics will be discussed in this text.

  19. Familial Myelodysplastic/Acute Leukemia Syndromes—Myeloid Neoplasms with Germline Predisposition

    OpenAIRE

    Baptista, Renata Lyrio Rafael; dos Santos, Anna Cláudia Evangelista; Gutiyama, Luciana Mayumi; Solza, Cristiana; Zalcberg, Ilana Renault

    2017-01-01

    Although most cases of myeloid neoplasms are sporadic, a small subset has been associated with germline mutations. The 2016 revision of the World Health Organization classification included these cases in a myeloid neoplasm group with a predisposing germline mutational background. These patients must have a different management and their families should get genetic counseling. Cases identification and outline of the major known syndromes characteristics will be discussed in this text.

  20. The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia

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    Zhang Xiaolu

    2012-08-01

    Full Text Available Abstract Background Recent evidence has accumulated that MicroRNA (miRNA dysregulation occurs in the majority of human malignancies including acute myeloid leukemia (AML and may contribute to onco-/leukemo-genesis. Methods The expression levels of miR-370 and FoxM1 were assessed in 48 newly diagnosed AML patients, 40 AML patients in 1st complete remission (CR and 21 healthy controls. Quantitative real-time PCR, western blots, colony formation assay, and β-Galactosidase ( SA-β-Gal staining were used to characterize the changes induced by overexpression or inhibition of miR-370 or FoxM1. Results We found that the down-regulation of miR-370 expression was a frequent event in both leukemia cell lines and primary leukemic cells from patients with de novo AML. Lower levels of miR-370 expression were found in 37 of 48 leukemic samples from AML patients compared to those in bone marrow cells derived from healthy adult individuals. Ectopic expression of miR-370 in HL60 and K562 cells led to cell growth arrest and senescence. In contrast, depletion of miR-370 expression using RNA interference enhanced the proliferation of those leukemic cells. Mechanistically, miR-370 targets the transcription factor FoxM1, a well established oncogenic factor promoting cell cycle progression. Moreover, when HL60 and K562 cells were treated with 5-aza-2′-deoxycytidine, a DNA methylation inhibitor, miR-370 expression was up-regulated, which indicates epigenetic silencing of miR-370 in leukemic cells. Conclusions Taken together, miR-370 may function as a tumor suppressor by targeting FoxM1, and the epigenetic silence of miR-370 thus leads to derepression of FoxM1 expression and consequently contributes to AML development and progression.

  1. Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia.

    Science.gov (United States)

    Zhu, Liuluan; Kong, Yaxian; Zhang, Jianhong; Claxton, David F; Ehmann, W Christopher; Rybka, Witold B; Palmisiano, Neil D; Wang, Ming; Jia, Bei; Bayerl, Michael; Schell, Todd D; Hohl, Raymond J; Zeng, Hui; Zheng, Hong

    2017-06-19

    T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1 + T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.

  2. Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia

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    Liuluan Zhu

    2017-06-01

    Full Text Available Abstract Background T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM domain (TIGIT and programmed cell death protein 1 (PD-1 are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML. In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1 in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Methods Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Results Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Conclusions Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.

  3. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia.

    Science.gov (United States)

    Stein, Eytan M; Walter, Roland B; Erba, Harry P; Fathi, Amir T; Advani, Anjali S; Lancet, Jeffrey E; Ravandi, Farhad; Kovacsovics, Tibor; DeAngelo, Daniel J; Bixby, Dale; Faderl, Stefan; Jillella, Anand P; Ho, Phoenix A; O'Meara, Megan M; Zhao, Baiteng; Biddle-Snead, Charles; Stein, Anthony S

    2018-01-25

    Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 µg/kg) or on days 1 and 4 (20 µg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years [range, 26-89 years]) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/µL) and 10.6 weeks for platelets (≥100 × 10 9 /L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329. © 2018 by The American Society of Hematology.

  4. The role of peptide and DNA vaccines in myeloid leukemia immunotherapy

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    Lin Chen

    2013-02-01

    Full Text Available Abstract While chemotherapy and targeted therapy are successful in inducing the remission of myeloid leukemia as acute myeloid leukemia (AML and chronic myeloid leukemia (CML, the disease remains largely incurable. This observation is likely due to the drug resistance of leukemic cells, which are responsible for disease relapse. Myeloid leukemia vaccines may most likely be beneficial for eradicating minimal residual disease after treatment with chemotherapy or targeted therapy. Several targeted immunotherapies using leukemia vaccines have been heavily investigated in clinical and preclinical trials. This review will focus on peptides and DNA vaccines in the context of myeloid leukemias, and optimal strategies for enhancing the efficacy of vaccines based on myeloid leukemia immunization are also summarized.

  5. Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

    DEFF Research Database (Denmark)

    Nicolini, Franck E; Mauro, Michael J; Martinelli, Giovanni

    2009-01-01

    The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP...

  6. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

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    Laura Guerenne

    2016-01-01

    Full Text Available Abstract Background In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. Methods We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS and acute myeloid leukemia (AML post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Results Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. Conclusions These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  7. Favorable clinical outcome and unique characteristics in association with Twist1 overexpression in de novo acute myeloid leukemia

    International Nuclear Information System (INIS)

    Chen, C-C; You, J-Y; Gau, J-P; Huang, C-E; Chen, Y-Y; Tsai, Y-H; Chou, H-J; Lung, J; Yang, M-H

    2015-01-01

    Epithelial–mesenchymal transition (EMT) is a critical process for inducing stem-like properties of epithelial cancer cells. However, the role of EMT inducers in hematological malignancies is unknown. Twist1, an EMT inducer necessary for cell migration, has recently been found to have transcriptionally regulatory activity on the expression of Bmi1, and these two are capable of promoting tumorigenesis in a synergized manner. Knowing that Bmi1 expression is essential for maintenance of leukemic stem cells, we speculate that Twist1 might govern the pathogenesis of acute myeloid leukemia (AML) development as well. We found that upregulated Twist1 increased Bmi1 expression in AML and endued leukemic cells a higher proliferative potential and increased resistance to apoptosis. In primary AML samples, there was strong positive correlation between the expression levels of Twist1 and Bmi1. AML patients whose leukemic blasts harbored overexpressed Twist1 had a more aggressive clinical phenotype, but they were more likely to have a better clinical outcome after standard therapy. In vitro studies confirmed that Twist1-overexpressing leukemic cells were more susceptible to cytarabine, but not daunorubicin, cytotoxicity. Our findings suggest that, in a subset of AML patients, Twist1 has a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes

  8. Reduction in WT1 gene expression during early treatment predicts the outcome in patients with acute myeloid leukemia.

    Science.gov (United States)

    Andersson, Charlotta; Li, Xingru; Lorenz, Fryderyk; Golovleva, Irina; Wahlin, Anders; Li, Aihong

    2012-12-01

    Wilms tumor gene 1 (WT1) expression has been suggested as an applicable minimal residual disease marker in acute myeloid leukemia (AML). We evaluated the use of this marker in 43 adult AML patients. Quantitative assessment of WT1 gene transcripts was performed using real-time quantitative-polymerase chain reaction assay. Samples from both the peripheral blood and the bone marrow were analyzed at diagnosis and during follow-up. A strong correlation was observed between WT1 normalized with 2 different control genes (β-actin and ABL1, P0.05). A≥1-log reduction in WT1 expression in bone marrow samples taken freedom from relapse (P=0.010) when β-actin was used as control gene. Furthermore, a reduction in WT1 expression by ≥2 logs in peripheral blood samples taken at a later time point significantly correlated with a better outcome for overall survival (P=0.004) and freedom from relapse (P=0.012). This result was achieved when normalizing against both β-actin and ABL1. These results therefore suggest that WT1 gene expression can provide useful information for minimal residual disease detection in adult AML patients and that combined use of control genes can give more informative results.

  9. The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells

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    Isabel Gonçalves Silva

    2017-08-01

    Full Text Available Acute myeloid leukemia (AML is a severe and often fatal systemic malignancy. Malignant cells are capable of escaping host immune surveillance by inactivating cytotoxic lymphoid cells. In this work we discovered a fundamental molecular pathway, which includes ligand-dependent activation of ectopically expressed latrophilin 1 and possibly other G-protein coupled receptors leading to increased translation and exocytosis of the immune receptor Tim-3 and its ligand galectin-9. This occurs in a protein kinase C and mTOR (mammalian target of rapamycin-dependent manner. Tim-3 participates in galectin-9 secretion and is also released in a free soluble form. Galectin-9 impairs the anti-cancer activity of cytotoxic lymphoid cells including natural killer (NK cells. Soluble Tim-3 prevents secretion of interleukin-2 (IL-2 required for the activation of cytotoxic lymphoid cells. These results were validated in ex vivo experiments using primary samples from AML patients. This pathway provides reliable targets for both highly specific diagnosis and immune therapy of AML.

  10. Selecting Sample Preparation Workflows for Mass Spectrometry-Based Proteomic and Phosphoproteomic Analysis of Patient Samples with Acute Myeloid Leukemia.

    Science.gov (United States)

    Hernandez-Valladares, Maria; Aasebø, Elise; Selheim, Frode; Berven, Frode S; Bruserud, Øystein

    2016-08-22

    Global mass spectrometry (MS)-based proteomic and phosphoproteomic studies of acute myeloid leukemia (AML) biomarkers represent a powerful strategy to identify and confirm proteins and their phosphorylated modifications that could be applied in diagnosis and prognosis, as a support for individual treatment regimens and selection of patients for bone marrow transplant. MS-based studies require optimal and reproducible workflows that allow a satisfactory coverage of the proteome and its modifications. Preparation of samples for global MS analysis is a crucial step and it usually requires method testing, tuning and optimization. Different proteomic workflows that have been used to prepare AML patient samples for global MS analysis usually include a standard protein in-solution digestion procedure with a urea-based lysis buffer. The enrichment of phosphopeptides from AML patient samples has previously been carried out either with immobilized metal affinity chromatography (IMAC) or metal oxide affinity chromatography (MOAC). We have recently tested several methods of sample preparation for MS analysis of the AML proteome and phosphoproteome and introduced filter-aided sample preparation (FASP) as a superior methodology for the sensitive and reproducible generation of peptides from patient samples. FASP-prepared peptides can be further fractionated or IMAC-enriched for proteome or phosphoproteome analyses. Herein, we will review both in-solution and FASP-based sample preparation workflows and encourage the use of the latter for the highest protein and phosphorylation coverage and reproducibility.

  11. Immunotherapeutic Concepts to Target Acute Myeloid Leukemia: Focusing on the Role of Monoclonal Antibodies, Hypomethylating Agents and the Leukemic Microenvironment

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    Olumide Babajide Gbolahan

    2017-07-01

    Full Text Available Intensive chemotherapeutic protocols and allogeneic stem cell transplantation continue to represent the mainstay of acute myeloid leukemia (AML treatment. Although this approach leads to remissions in the majority of patients, long-term disease control remains unsatisfactory as mirrored by overall survival rates of approximately 30%. The reason for this poor outcome is, in part, due to various toxicities associated with traditional AML therapy and the limited ability of most patients to tolerate such treatment. More effective and less toxic therapies therefore represent an unmet need in the management of AML, a disease for which therapeutic progress has been traditionally slow when compared to other cancers. Several studies have shown that leukemic blasts elicit immune responses that could be exploited for the development of novel treatment concepts. To this end, early phase studies of immune-based therapies in AML have delivered encouraging results and demonstrated safety and feasibility. In this review, we discuss opportunities for immunotherapeutic interventions to enhance the potential to achieve a cure in AML, thereby focusing on the role of monoclonal antibodies, hypomethylating agents and the leukemic microenvironment.

  12. SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models.

    Science.gov (United States)

    Hengst, Jeremy A; Dick, Taryn E; Sharma, Arati; Doi, Kenichiro; Hegde, Shailaja; Tan, Su-Fern; Geffert, Laura M; Fox, Todd E; Sharma, Arun K; Desai, Dhimant; Amin, Shantu; Kester, Mark; Loughran, Thomas P; Paulson, Robert F; Claxton, David F; Wang, Hong-Gang; Yun, Jong K

    2017-01-01

    To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178. Using the state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect "direct target engagement" of proteins intact cells, in vitro and in vivo assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML). Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2. We also present evidence that, in addition to its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a microtubule network disrupting agent both in vitro and in intact cells. Interestingly, we separately demonstrate that simultaneous SphK inhibition and microtubule disruption synergistically induces apoptosis in AML cell lines. Furthermore, we demonstrate that SKI-178 is well tolerated in normal healthy mice. Most importantly, we demonstrate that SKI-178 has therapeutic efficacy in several mouse models of AML. SKI-178 is a multi-targeted agent that functions both as an inhibitor of the SphKs as well as a disruptor of the microtubule network. SKI-178 induced apoptosis arises from a synergistic interaction of these two activities. SKI-178 is safe and effective in mouse models of AML, supporting its further development as a multi-targeted anti-cancer therapeutic agent.

  13. Small RNA sequencing profiles of mir-181 and mir-221, the most relevant microRNAs in acute myeloid leukemia.

    Science.gov (United States)

    Lee, Yun-Gyoo; Kim, Inho; Oh, Somi; Shin, Dong-Yeop; Koh, Youngil; Lee, Keun-Wook

    2017-11-27

    To evaluate and select microRNAs relevant to acute myeloid leukemia (AML) pathogenesis, we analyzed differential microRNA expression by quantitative small RNA next-generation sequencing using duplicate marrow samples from individual AML patients. For this study, we obtained paired marrow samples at two different time points (initial diagnosis and first complete remission status) in patients with AML. Bone marrow microRNAs were profiled by next-generation small RNA sequencing. Quantification of microRNA expression was performed by counting aligned reads to microRNA genes. Among 38 samples (32 paired samples from 16 AML patients and 6 normal marrow controls), 27 were eligible for sequencing. Small RNA sequencing showed that 12 microRNAs were selectively expressed at higher levels in AML patients than in normal controls. Among these 12 microRNAs, mir-181, mir-221, and mir-3154 were more highly expressed at initial AML diagnosis as compared to first complete remission. Significant correlations were found between higher expression levels of mir-221, mir-146, and mir-155 and higher marrow blast counts. Our results demonstrate that mir-221 and mir-181 are selectively enriched in AML marrow and reflect disease activity. mir-3154 is a novel microRNA that is relevant to AML but needs further validation.

  14. The Role of Azacitidine in the Treatment of Elderly Patients with Acute Myeloid Leukemia: Results of a Retrospective Multicenter Study

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    Anıl Tombak

    2016-12-01

    Full Text Available Objective: In this study, we aimed to investigate the efficacy and safety of azacitidine (AZA in elderly patients with acute myeloid leukemia (AML, including patients with >30% bone marrow (BM blasts. Materials and Methods: In this retrospective multicenter study, 130 patients of ≥60 years old who were ineligible for intensive chemotherapy or had progressed despite conventional treatment were included. Results: The median age was 73 years and 61.5% of patients had >30% BM blasts. Patients received AZA for a median of four cycles (range: 1-21. Initial overall response [including complete remission (CR/CR with incomplete recovery/partial remission] was 36.2%. Hematologic improvement (HI of any kind was documented in 37.7% of all patients. HI was also documented in 27.1% of patients who were unresponsive to treatment.nMedian overall survival (OS was 18 months for responders and 12 months for nonresponders (p=0.005. In the unresponsive patient group, any HI improved OS compared to patients without any HI (median OS was 14 months versus 10 months, p=0.068. Eastern Cooperative Oncology Group performance status of <2, increasing number of AZA cycles (≥5 courses, and any HI predicted better OS. Age, AML type, and BM blast percentage had no impact. Conclusion: We conclude that AZA is effective and well tolerated in elderly comorbid AML patients, irrespective of BM blast count, and HI should