Genetic Analysis of Transforming Events That Convert Chronic Myeloproliferative Neoplasms to Leukemias

Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer Research (Impact Factor: 9.33). 01/2010; 70(2):447-52. DOI: 10.1158/0008-5472.CAN-09-3783
Source: PubMed


The oncogenetic events that transform chronic myeloproliferative neoplasms (MPN) to acute myeloid leukemias (AML) are not well characterized. We investigated the role of several genes implicated in leukemic transformation by mutational analysis of 63 patients with AML secondary to a preexisting MPN (sAML). Frequent mutations were identified in TET2 (26.3%), ASXL1 (19.3%), IDH1 (9.5%), and JAK2 (36.8%) mutations in sAML, and all possible mutational combinations of these genes were also observed. Analysis of 14 patients for which paired samples from MPN and sAML were available showed that TET2 mutations were frequently acquired at leukemic transformation [6 of 14 (43%)]. In contrast, ASXL1 mutations were almost always detected in both the MPN and AML clones from individual patients. One case was also observed where TET2 and ASXL1 mutations were found before the patient acquired a JAK2 mutation or developed clinical evidence of MPN. We conclude that mutations in TET2, ASXL1, and IDH1 are common in sAML derived from a preexisting MPN. Although TET2/ASXL1 mutations may precede acquisition of JAK2 mutations by the MPN clone, mutations in TET2, but not ASXL1, are commonly acquired at the time of leukemic transformation. Our findings argue that the mutational order of events in MPN and sAML varies in different patients, and that TET2 and ASXL1 mutations have distinct roles in MPN pathogenesis and leukemic transformation. Given the presence of sAML that have no preexisting JAK2/TET2/ASXL1/IDH1 mutations, our work indicates the existence of other mutations yet to be identified that are necessary for leukemic transformation.

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Available from: Taghi Manshouri, Oct 04, 2015
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    • "ASXL-1 mutations are frequently detected at diagnosis of MDS and MPN and remain constant throughout disease progression [46]. Despite one study which found increased mutation incidence in myelofibrosis secondary to other MPNs, evidence suggests that ASXL-1 mutations are early events which may precede JAK2 and TET2 mutations [46] [73]. ASXL-1 mutations—particularly frameshift—are associated with more aggressive disease, faster time to leukemic transformation and shorter overall survival in MPN and MDS [71] [81]. "
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    ABSTRACT: 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.
    Advances in Hematology 03/2014; 2014(8):103175. DOI:10.1155/2014/103175
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    • "ASXL1 mutations correlated with progression to blast-state in myelodysplastic syndromes and chronic myelomonocytic leukaemia [9,10] while in MF, they are detectable in most patients at diagnosis [11], and they are present in chronic- and blast-phases [2] with the same prevalence [6]. These findings suggest that ASXL1 mutations play a crucial role in the pathogenesis of MF [6,11] but they do not directly cause a leukemic phenotype [2,6]. We here characterize the molecular changes associated to the leukemic transformation of a patient with primary-MF (PMF) using next-generation sequencing (NGS). "
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    ABSTRACT: We have characterized the molecular changes underlying the transformation of a JAK2V617F +-myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F +-clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of myelofibrosis.
    Journal of Hematology & Oncology 09/2013; 6(1):68. DOI:10.1186/1756-8722-6-68 · 4.81 Impact Factor
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    • "In the absence of wild-type functional CBL, c-CBL mutants cause a GOF effect and hypersensitivity to various cytokines including SCF, TPO, FLT3 ligand, and IL-3. However, the functional significance of these findings in the pathogenesis of MPN is unknown [83, 84]. "
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    ABSTRACT: Myeloproliferative neoplasms (MPN) are debilitating stem cell-derived clonal myeloid malignancies. Conventional treatments for the BCR-ABL1-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) have, so far, been unsatisfactory. Following the discovery of dysregulated JAK-STAT signaling in patients with MPN, many efforts have been directed toward the development of molecularly targeted therapies, including inhibitors of JAK1 and JAK2. Ruxolitinib (previously known as INCB018424; Incyte Corporation, Wilmington, Delaware, USA) is a rationally designed potent and selective oral JAK1 and JAK2 inhibitor that has undergone clinical trials in patients with PV, ET, and PMF. Ruxolitinib was approved on November 16, 2011 by the United States Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis (MF), including patients with PMF, post-PV MF, and post-ET MF. In randomized phase III studies, ruxolitinib treatment resulted in significant and durable reductions in splenomegaly and improvements in disease-related symptoms in patients with MF compared with placebo or best available therapy. The most common adverse events were anemia and thrombocytopenia, which were manageable and rarely led to discontinuation. This review addresses the cellular and molecular biology, and the clinical management of MPN.
    Current Medicinal Chemistry 07/2012; 19(26). DOI:10.2174/092986712803251511 · 3.85 Impact Factor
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