title: Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.
abstract: 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.
authors.affiliation: Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.forename: Kelly
authors.initials: K
authors.lastname: Harris
authors.forename: Jinjuan
authors.initials: J
authors.lastname: Yao
authors.forename: Cyrus
authors.initials: C
authors.lastname: Hedvat
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2