Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm

Blood. 2010 Apr 8;115(14):2891-900. doi: 10.1182/blood-2009-08-236596. Epub 2009 Dec 11.

Abstract

Acute myeloid leukemia (AML) may follow a JAK2-positive myeloproliferative neoplasm (MPN), although the mechanisms of disease evolution, often involving loss of mutant JAK2, remain obscure. We studied 16 patients with JAK2-mutant (7 of 16) or JAK2 wild-type (9 of 16) AML after a JAK2-mutant MPN. Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only 1 of 9 JAK2 wild-type AMLs (P = .001), implying that JAK2-mutant AML is preceded by mutation(s) that give rise to a "myelofibrosis" phenotype. Loss of the JAK2 mutation by mitotic recombination, gene conversion, or deletion was excluded in all wild-type AMLs. A search for additional mutations identified alterations of RUNX1, WT1, TP53, CBL, NRAS, and TET2, without significant differences between JAK2-mutant and wild-type leukemias. In 4 patients, mutations in TP53, CBL, or TET2 were present in JAK2 wild-type leukemic blasts but absent from the JAK2-mutant MPN. By contrast in a chronic-phase patient, clones harboring mutations in JAK2 or MPL represented the progeny of a shared TET2-mutant ancestral clone. These results indicate that different pathogenetic mechanisms underlie transformation to JAK2 wild-type and JAK2-mutant AML, show that TET2 mutations may be present in a clone distinct from that harboring a JAK2 mutation, and emphasize the clonal heterogeneity of the MPNs.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blast Crisis / genetics*
  • Blast Crisis / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Hematologic Neoplasms / genetics*
  • Hematologic Neoplasms / metabolism
  • Humans
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / metabolism
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasms, Second Primary / genetics*
  • Neoplasms, Second Primary / metabolism
  • Primary Myelofibrosis / genetics*
  • Primary Myelofibrosis / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • TET2 protein, human
  • Proto-Oncogene Proteins c-cbl
  • JAK2 protein, human
  • Janus Kinase 2
  • CBL protein, human