Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid Transformation

Kelly Moran-Crusio, Linsey Reavie, Alan Shih, Omar Abdel-Wahab, Delphine Ndiaye-Lobry, Camille Lobry, Maria E. Figueroa, Aparna Vasanthakumar, Jay Patel, Xinyang Zhao, Fabiana Perna, Suveg Pandey, Jozef Madzo, Chunxiao Song, Qing Dai, Chuan He, Sherif Ibrahim, Miloslav Beran, Jiri Zavadil, Stephen D. NimerAri Melnick, Lucy A. Godley, Iannis Aifantis*, Ross L. Levine

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1068 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11-24
Number of pages14
JournalCancer cell
Volume20
Issue number1
DOIs
StatePublished - Jul 12 2011

Funding

We would like to thank Hans-Guido Wendel and Dino Mavrakis for assistance with Tet2 shRNA construction. Also, we thank the NYU Genome Technology Center (supported in part by NIH/NCI P30 CA016087-30 grant) for expert assistance with microarray experiments, and the NYU Flow Cytometry facility (supported in part by NIH/NCI 5 P30CA16087-31) for expert cell sorting, the NYU Histology Core (5P30CA16087-31), and the Transgenic Mouse Core (NYU Cancer Institute Center Grant [5P30CA16087-31]). I.A. is supported by the National Institutes of Health (RO1CA133379, RO1CA105129, R21CA141399, RO1CA149655, RO1GM088847), the Leukemia & Lymphoma Society (TRP grant), the American Cancer Society (RSG0806801), the Irma T. Hirschl Trust, and the Dana Foundation. This work was supported in part by grants from the National Institutes of Health (U54CA143798-01, Physical Sciences Oncology Center) and 1R01CA138234-01, and by grants from the Starr Cancer Consortium and Howard Hughes Medical Institute to R.L.L. L.R. is supported by a NIH Ruth L. Kirchstein Award (F31-AG039991). M.E.F. is funded by a Leukemia and Lymphoma Society Special Fellow award. A.M. is funded by a Leukemia and Lymphoma Society SCOR and TRP award, and is a Burroughs Wellcome Clinical Translational Scholar and Scholar of the Leukemia and Lymphoma Society. A.M. and M.E.F. are also supported by the Sackler Center for Biomedical and Physical Sciences. L.A.G. was supported by the NIH Grants CA129831 and CA129831-03S1. X.Z. and S.D.N. are supported by a Leukemia and Lymphoma Society SCOR award and FP by an American Italian Cancer Foundation award. R.L.L. is a Geoffrey Beene Junior Faculty Chair at Memorial Sloan-Kettering Cancer Center. I.A. is a Howard Hughes Medical Institute Early Career Scientist.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Cell Biology

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