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

Philip A Beer, François Delhommeau, Jean-Pierre LeCouédic, Mark A Dawson, Edwin Chen, David Bareford, Rajko Kusec, Mary Frances McMullin, Claire N Harrison, Alessandro M Vannucchi, William Vainchenker, Anthony R Green

Research output: Contribution to journalArticle

190 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2891-2900
Number of pages10
JournalBlood
Volume115
Issue number14
DOIs
Publication statusPublished - 08 Apr 2010

Keywords

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

Fingerprint Dive into the research topics of 'Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm'. Together they form a unique fingerprint.

  • Cite this

    Beer, P. A., Delhommeau, F., LeCouédic, J-P., Dawson, M. A., Chen, E., Bareford, D., Kusec, R., McMullin, M. F., Harrison, C. N., Vannucchi, A. M., Vainchenker, W., & Green, A. R. (2010). Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood, 115(14), 2891-2900. https://doi.org/10.1182/blood-2009-08-236596