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

Abstract

<div>Abstract<p>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 <i>TET2</i> (26.3%), <i>ASXL1</i> (19.3%), <i>IDH1</i> (9.5%), and <i>JAK2</i> (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 <i>TET2</i> 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 <i>TET2</i> and <i>ASXL1</i> mutations were found before the patient acquired a <i>JAK2</i> mutation or developed clinical evidence of MPN. We conclude that mutations in <i>TET2, ASXL1</i>, and <i>IDH1</i> are common in sAML derived from a preexisting MPN. Although <i>TET2/ASXL1</i> mutations may precede acquisition of <i>JAK2</i> mutations by the MPN clone, mutations in <i>TET2</i>, but not <i>ASXL1</i>, 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 <i>TET2</i> and <i>ASXL1</i> mutations have distinct roles in MPN pathogenesis and leukemic transformation. Given the presence of sAML that have no preexisting <i>JAK2/TET2/ASXL1/IDH1</i> mutations, our work indicates the existence of other mutations yet to be identified that are necessary for leukemic transformation. Cancer Res; 70(2); 447–52</p></div>