Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms

Blood. 2010 Mar 11;115(10):2003-7. doi: 10.1182/blood-2009-09-245381. Epub 2010 Jan 8.

Abstract

Somatic mutations in TET2 occur in patients with myeloproliferative neoplasms and other hematologic malignancies. It has been suggested that TET2 is a tumor suppressor gene and mutations in TET2 precede the acquisition of JAK2-V617F. To examine the order of events, we performed colony assays and genotyped TET2 and JAK2 in individual colonies. In 4 of 8 myeloproliferative neoplasm patients, we found that some colonies with mutated TET2 carried wild-type JAK2, whereas others were JAK2-V617F positive, indicating that TET2 occurred before JAK2-V617F. One of these patients carried a germline TET2 mutation. However, in 2 other patients, we obtained data compatible with the opposite order of events, with JAK2 exon 12 mutation preceding TET2 mutation in one case. Finally, in 2 of 8 patients, the TET2 and JAK2-V617F mutations defined 2 separate clones. The lack of a strict temporal order of occurrence makes it unlikely that mutations in TET2 represent a predisposing event for acquiring mutations in JAK2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Separation / methods
  • Clone Cells / metabolism
  • Clone Cells / pathology*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Dioxygenases
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / pathology
  • Humans
  • Janus Kinase 2 / genetics*
  • Male
  • Middle Aged
  • Mutation* / physiology
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / pathology
  • Polymorphism, Single Nucleotide / physiology
  • Proto-Oncogene Proteins / genetics*
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Dioxygenases
  • TET2 protein, human
  • JAK2 protein, human
  • Janus Kinase 2