ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice

EMBO J. 2010 Dec 15;29(24):4118-31. doi: 10.1038/emboj.2010.292. Epub 2010 Nov 26.

Abstract

Reactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3(-/-) HPs in vivo. Our combined results show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression.

Publication types

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

MeSH terms

  • Acetylcysteine / therapeutic use
  • Animals
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / deficiency*
  • Free Radical Scavengers / therapeutic use
  • Gene Expression Regulation
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Myeloproliferative Disorders / drug therapy
  • Myeloproliferative Disorders / pathology*
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Splenomegaly / pathology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Free Radical Scavengers
  • Intracellular Signaling Peptides and Proteins
  • Lnk protein, mouse
  • Membrane Proteins
  • Proteins
  • Reactive Oxygen Species
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Acetylcysteine