Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm

Blood. 2016 Jun 30;127(26):3410-23. doi: 10.1182/blood-2015-11-679431. Epub 2016 Apr 14.

Abstract

An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera-like disease, concomitant loss of Ezh2 significantly reduced the red blood cell and hematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion of megakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617F-expressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, and Hmga2 were transcriptionally derepressed, and the H3K27me3 levels in these gene promoters were significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617F mice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increased megakaryocytic colonies in the BM of Jak2V617F mice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Enhancer of Zeste Homolog 2 Protein / deficiency*
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Hematologic Neoplasms* / genetics
  • Hematologic Neoplasms* / metabolism
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • Megakaryocyte Progenitor Cells / metabolism
  • Megakaryocyte Progenitor Cells / pathology
  • Mice
  • Mice, Transgenic
  • Mutation, Missense*
  • Platelet Count
  • Primary Myelofibrosis / genetics
  • Primary Myelofibrosis / metabolism*
  • Primary Myelofibrosis / pathology

Substances

  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Jak2 protein, mouse
  • Janus Kinase 2