Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation

Cancer Cell. 2011 Jul 12;20(1):11-24. doi: 10.1016/j.ccr.2011.06.001. Epub 2011 Jun 30.

Abstract

Somatic loss-of-function mutations in the ten-eleven translocation 2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in hematopoietic development have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment that leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2(+/-) mice also displayed increased stem cell self-renewal and extramedullary hematopoiesis, suggesting that Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / metabolism
  • Gene Deletion
  • Gene Knockout Techniques
  • Gene Silencing
  • Haploinsufficiency / genetics
  • Hematopoiesis
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology*
  • Humans
  • Leukemia, Myelomonocytic, Chronic / pathology
  • Mice
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology*
  • Proto-Oncogene Proteins / deficiency*
  • Proto-Oncogene Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET2 protein, human
  • Tet2 protein, mouse