Stat3 promotes the development of erythroleukemia by inducing Pu.1 expression and inhibiting erythroid differentiation

Oncogene. 2009 Sep 24;28(38):3349-59. doi: 10.1038/onc.2009.202. Epub 2009 Jul 6.

Abstract

Leukemogenesis requires two classes of mutations, one that promotes proliferation and one that blocks differentiation. The erythroleukemia induced by Friend virus is a multistage disease characterized by an early proliferative stage driven by the interaction of the viral glycoprotein, gp55, with Sf-Stk and the EpoR, and a late block to differentiation resulting from retroviral insertion in the Pu.1 locus. We demonstrate here that activation of Stat3 by Sf-Stk in the early stage of disease is essential for the progression of erythroleukemia in the presence of differentiation signals induced by the EpoR, but is dispensable in the late stages of the disease. Furthermore, we identify Pu.1 as a Stat3 target gene in the early stages of erythroleukemia development. Our results support a model whereby the activation of Stat3 in the early stage of disease plays a pivotal role in regulating differentiation through the upregulation of Pu.1, thus inhibiting differentiation and favoring the expansion of infected erythroblasts and enhancing the pool of progenitors available for the acquisition of additional mutations, including insertional activation of Pu.1, resulting in full leukemic transformation.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Differentiation
  • Erythroblasts / cytology*
  • Friend murine leukemia virus
  • Gene Expression Regulation*
  • Leukemia, Erythroblastic, Acute / etiology*
  • Mice
  • Mice, Inbred BALB C
  • Phosphoproteins / physiology
  • Proto-Oncogene Proteins / genetics*
  • STAT3 Transcription Factor / physiology*
  • Trans-Activators / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Gab2 protein, mouse
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • proto-oncogene protein Spi-1