MPN patients harbor recurrent truncating mutations in transcription factor NF-E2

J Exp Med. 2013 May 6;210(5):1003-19. doi: 10.1084/jem.20120521.

Abstract

The molecular etiology of myeloproliferative neoplasms (MPNs) remains incompletely understood, despite recent advances incurred through the discovery of several different mutations in MPN patients. We have recently described overexpression of the transcription factor NF-E2 in MPN patients and shown that elevated NF-E2 levels in vivo cause an MPN phenotype and predispose to leukemic transformation in transgenic mice. We report the presence of acquired insertion and deletion mutations in the NF-E2 gene in MPN patients. These result in truncated NF-E2 proteins that enhance wild-type (WT) NF-E2 function and cause erythrocytosis and thrombocytosis in a murine model. NF-E2 mutant cells acquire a proliferative advantage, witnessed by clonal dominance over WT NF-E2 cells in MPN patients. Our data underscore the role of increased NF-E2 activity in the pathophysiology of MPNs.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Neoplasms / genetics*
  • Bone Marrow Neoplasms / pathology
  • Bone Marrow Transplantation
  • Cell Lineage / genetics
  • Cell Proliferation
  • Clone Cells
  • DNA / metabolism
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Janus Kinase 2 / metabolism
  • Mice
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / pathology
  • NF-E2 Transcription Factor, p45 Subunit / genetics*
  • NF-E2 Transcription Factor, p45 Subunit / metabolism
  • Protein Binding / genetics
  • Protein Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcriptional Activation / genetics

Substances

  • Mutant Proteins
  • NF-E2 Transcription Factor, p45 Subunit
  • NFE2 protein, human
  • RNA, Messenger
  • DNA
  • Janus Kinase 2