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Epigenetics Mar 2019Juvenile myelomonocytic leukemia (JMML) stands out among malignant neoplasms of childhood in several ways. First, JMML is a model condition to elucidate the relevance of... (Review)
Review
Juvenile myelomonocytic leukemia (JMML) stands out among malignant neoplasms of childhood in several ways. First, JMML is a model condition to elucidate the relevance of deregulated Ras signal transduction in human cancer. Second, the identification of Ras pathway mutations in JMML has informed the field of germline cancer predisposition and advanced the understanding of molecular mechanisms underlying the progression from predisposition to neoplasia. Third and not least, genomic DNA methylation was discovered to play a salient role in the classification and prognostication of the disease. This article discusses the evolution of epigenetic research on JMML over the past years and reviews the relevance of aberrant DNA methylation in the diagnosis, concept, and clinical decision-making of JMML.
Topics: Antimetabolites, Antineoplastic; Azacitidine; Child; DNA Methylation; Epigenesis, Genetic; Humans; Leukemia, Myelomonocytic, Juvenile; Mutation
PubMed: 30773984
DOI: 10.1080/15592294.2019.1583039 -
Blood Nov 2016Exome sequencing studies in chronic myelomonocytic leukemia (CMML) illustrate a mutational landscape characterized by few somatic mutations involving a subset of... (Review)
Review
Exome sequencing studies in chronic myelomonocytic leukemia (CMML) illustrate a mutational landscape characterized by few somatic mutations involving a subset of recurrent gene mutations in ASXL1, SRSF2, and TET2, each approaching 40% in incidence. This has led to the clinical implementation of next-generation sequencing panels that effectively identify clonal monocytosis and complement clinical prognostic scoring systems in most patients. However, most murine models based on single gene mutations fail to recapitulate the CMML phenotype, and many gene mutations are loss of function, making the identification of traditional therapeutic vulnerabilities challenging. Further, as a subtype of the myelodysplastic/myeloproliferative neoplasms, CMML has a complex clinical heterogeneity not reflected by the mutational landscape. In this review, we will discuss the discordance between mutational homogeneity and clinical complexity and highlight novel genomic and nongenomic approaches that offer insight into the underlying clinical characteristics of CMML.
Topics: Disease Progression; Genetic Heterogeneity; Genomics; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myelomonocytic, Chronic; Mutation; Phenotype; Prognosis
PubMed: 27707735
DOI: 10.1182/blood-2016-07-692988 -
Haematologica Sep 2013With the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to... (Review)
Review
With the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to the criterion of clinical relevance. Recommendations were produced using a Delphi process and four consensus conferences involving a panel of experts appointed by the Italian Society of Hematology and affiliated societies. This report presents the final statements and recommendations, covering patient evaluation at diagnosis, diagnostic criteria, risk classification, first-line therapy, monitoring, second-line therapy and allogeneic stem cell transplantation. For the first-line therapy, the panel recommended that patients with myelodysplastic-type chronic myelomonocytic leukemia and less than 10% blasts in bone marrow should be managed with supportive therapy aimed at correcting cytopenias. In patients with myelodysplastic-type chronic myelomonocytic leukemia with a high number of blasts in bone marrow (≥ 10%), supportive therapy should be integrated with the use of 5-azacytidine. Patients with myeloproliferative-type chronic myelomonocytic leukemia with a low number of blasts (<10%) should be treated with cytoreductive therapy. Hydroxyurea is the drug of choice to control cell proliferation and to reduce organomegaly. Patients with myeloproliferative-type chronic myelomonocytic leukemia, and a high number of blasts should receive polychemotherapy. Both in myelodysplastic-type and myeloproliferative-type chronic myelomonocytic leukemia, allogeneic stem cell transplantation should be offered within clinical trials in selected patients.
Topics: Consensus; Disease Management; Humans; Leukemia, Myelomonocytic, Chronic; Practice Guidelines as Topic; Societies, Medical; World Health Organization
PubMed: 24006407
DOI: 10.3324/haematol.2013.084020 -
British Journal of Haematology Mar 2018Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major... (Review)
Review
Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches.
Topics: Humans; Leukemia, Myelomonocytic, Acute; Leukemia, T-Cell; Myeloid Cells; Neoplasm Proteins; Precursor Cells, T-Lymphoid
PubMed: 29441563
DOI: 10.1111/bjh.15129 -
Haematologica Mar 2020
Topics: Cytogenetic Analysis; Cytogenetics; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile
PubMed: 32115412
DOI: 10.3324/haematol.2019.240853 -
Haematologica Jan 2020The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly...
The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34 cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in and two heterozygous mutations in in the founding clone and a secondary (G12D) mutation. CD34 cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the (G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Mutation; Myeloproliferative Disorders; Exome Sequencing
PubMed: 31048357
DOI: 10.3324/haematol.2018.208488 -
The Netherlands Journal of Medicine Mar 2012The development of immunological abnormalities in various neoplasms is a rather common phenomenon. The prevalence of life-threatening systemic vasculitis in malignancy,... (Review)
Review
The development of immunological abnormalities in various neoplasms is a rather common phenomenon. The prevalence of life-threatening systemic vasculitis in malignancy, however, is much lower. Nonetheless we found an unexpected frequency of several autoimmune manifestations, including systemic vasculitis, in certain myelodysplastic syndromes. We illustrate this finding with the case of a 43-year-old man with signs of polyarteritis nodosa-like systemic vasculitis during progression of chronic myelomonocytic leukaemia. Subsequently, we review the literature on the combination of myelodysplastic syndromes and systemic vasculitis and discuss the prognostic consequences, considerations for treatment and possible pathophysiological mechanisms.
Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Comorbidity; Humans; Immunosuppressive Agents; Leukemia, Myelomonocytic, Chronic; Male; Myelodysplastic Syndromes; Prognosis; Systemic Vasculitis
PubMed: 22418751
DOI: No ID Found -
Blood Apr 2001PU.1 is an Ets family transcription factor essential for myelomonocyte and B-cell development. We previously showed that overexpression of PU.1 in murine erythroleukemia...
PU.1 is an Ets family transcription factor essential for myelomonocyte and B-cell development. We previously showed that overexpression of PU.1 in murine erythroleukemia (MEL) cells inhibits growth and erythroid differentiation and induces apoptosis of the cells. In an effort to identify target genes of PU.1 concerning these phenomena by using a messenger RNA differential display strategy, we found that some myeloid-specific and lymphoid-specific genes, such as the osteopontin gene, are transcriptionally up-regulated in MEL cells after overexpression of PU.1. We then found that expression of several myelomonocyte-specific genes, including the CAAT-enhancer-binding protein-alpha and granulocyte-macrophage colony-stimulating factor receptor genes, was induced in MEL cells after overexpression of PU.1. B-cell-specific genes were also examined, and expression of the CD19 gene was found to be induced. Expression of the myelomonocyte-specific proteins CD11b and F4/80 antigen but not the B-cell-specific proteins B220 and CD19 was also induced. After overexpression of PU.1, MEL cells became adherent and phagocytic and showed enhanced nitroblue tetrazolium reduction activity. Expression of myelomonocyte-specific and B-cell-specific genes was not induced when a mutant PU.1 with part of the activation domain deleted (a change found to inhibit erythroid differentiation of MEL cells) was expressed. These results indicate that PU.1 induces a lineage switch in MEL cells toward myelomonocytic cells and that its activation domain is essential for this effect. The results also suggest that the pathway of the lineage switch is distinct from that of inhibition of erythroid differentiation in MEL cells.
Topics: Cell Adhesion; Cell Differentiation; Cell Lineage; Cell Size; Chlorides; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Leukemia, Erythroblastic, Acute; Neoplasm Proteins; Neoplastic Stem Cells; Protein Structure, Tertiary; Proto-Oncogene Proteins; RNA, Messenger; RNA, Neoplasm; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; Subtraction Technique; Trans-Activators; Transcription, Genetic; Zinc Compounds
PubMed: 11290591
DOI: 10.1182/blood.v97.8.2300 -
Haematologica Feb 2007
Topics: Benzamides; Chromosome Aberrations; Humans; Imatinib Mesylate; In Situ Hybridization, Fluorescence; Leukemia, Myelomonocytic, Chronic; Myeloproliferative Disorders; Piperazines; Proto-Oncogene Proteins c-ets; Pyrimidines; Receptor, Platelet-Derived Growth Factor beta; Remission Induction; Repressor Proteins; Translocation, Genetic; ETS Translocation Variant 6 Protein
PubMed: 17296561
DOI: 10.3324/haematol.11187 -
Blood Oct 2014Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells... (Review)
Review
Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukemia, a similar disease in adults. Although the current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transplant, relapse is the most frequent cause of treatment failure. Tremendous progress has been made in defining the genomic landscape of JMML. Insights from cancer predisposition syndromes have led to the discovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signaling pathway. This has improved our ability to accurately diagnose patients, develop molecular markers to measure disease burden, and choose therapeutic agents to test in clinical trials. This review emphasizes recent advances in the field, including mapping of the genomic and epigenome landscape, insights from new and existing disease models, targeted therapeutics, and future directions.
Topics: Animals; Child; Epigenesis, Genetic; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelomonocytic, Juvenile; Molecular Targeted Therapy
PubMed: 25163700
DOI: 10.1182/blood-2014-03-300319