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
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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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    • "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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    • "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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