Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias Journal Article

Authors: Abdel-Wahab, O.; Manshouri, T.; Patel, J.; Harris, K.; Yao, J.; Hedvat, C.; Heguy, A.; Bueso-Ramos, C.; Kantarjian, H.; Levine, R. L.; Verstovsek, S.
Article 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. ©2010 AACR.
Keywords: myeloproliferative disorders; gene mutation; major clinical study; sequence analysis; single nucleotide polymorphism; mutation; dna-binding proteins; leukemia, myeloid, acute; proto-oncogene proteins; janus kinase 2; pathogenesis; genetic analysis; neoplasm; genotype; chronic myeloid leukemia; mutational analysis; cell transformation, neoplastic; molecular cloning; dna mutational analysis; repressor proteins; genetic polymorphism; isocitrate dehydrogenase; chronic myeloproliferative neoplasm
Journal Title: Cancer Research
Volume: 70
Issue: 2
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2010-01-15
Start Page: 447
End Page: 452
Language: English
DOI: 10.1158/0008-5472.can-09-3783
PUBMED: 20068184
PROVIDER: scopus
PMCID: PMC2947340
Notes: --- - "Cited By (since 1996): 31" - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Adriana Heguy
    85 Heguy
  2. Cyrus Hedvat
    123 Hedvat
  3. Jinjuan Yao
    24 Yao
  4. Ross Levine
    490 Levine
  5. Jay Prakash Patel
    53 Patel
  6. Kelly Desmond Harris
    2 Harris