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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.

Original publication

DOI

10.1016/j.ccr.2011.06.001

Type

Journal article

Journal

Cancer Cell

Publication Date

12/07/2011

Volume

20

Pages

11 - 24

Keywords

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