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PMID: 21723200 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 20 ·No. 1 ·2011-07-12 ·Pages 11-24

Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Madzo J, Song C, Dai Q, He C, Ibrahim S, Beran M, Zavadil J, Nimer SD, Melnick A, Godley LA, Aifantis I, Levine RL

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.

MeSH Terms
Alleles Animals Cell Proliferation Cell Transformation, Neoplastic/metabolism,pathology DNA-Binding Proteins/deficiency,metabolism Dioxygenases Gene Deletion Gene Knockout Techniques Gene Silencing Haploinsufficiency/genetics Hematopoiesis Hematopoietic Stem Cells/metabolism,pathology Humans Leukemia, Myelomonocytic, Chronic/pathology Mice Myeloid Cells/metabolism,pathology Proto-Oncogene Proteins/deficiency,metabolism
Chemicals
DNA-Binding Proteins Proto-Oncogene Proteins Dioxygenases TET2 protein, human Tet2 protein, mouse
Authors & Affiliations
24 authors, click to expand affiliations / ORCID
Moran-Crusio Kelly
Department of Pathology, NYU Cancer Institute, New York University School of Medicine, NY 10016, USA.
Reavie Linsey
Shih Alan
Abdel-Wahab Omar
Ndiaye-Lobry Delphine
Lobry Camille
Figueroa Maria E
Vasanthakumar Aparna
Patel Jay
Zhao Xinyang
Perna Fabiana
Pandey Suveg
Madzo Jozef
Song Chunxiao
Dai Qing
He Chuan
Ibrahim Sherif
Beran Miloslav
Zavadil Jiri
Nimer Stephen D
Melnick Ari
Godley Lucy A
Aifantis Iannis
Levine Ross L
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2011.06.001
Published
2011-07-12
Epub
2011-00-30
Pages
11-24
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3194039
Subset
IM
Grants
NIA NIH HHS · F31 AG039991 · United States
Howard Hughes Medical Institute · United States
NIA NIH HHS · F31-AG039991 · United States
NCI NIH HHS · R21 CA141399 · United States
NCI NIH HHS · R01CA149655 · United States
NCI NIH HHS · CA129831 · United States
NCI NIH HHS · R01 CA105129-07 · United States
NCI NIH HHS · R01CA105129 · United States
NCI NIH HHS · P30 CA016087 · United States
NCI NIH HHS · U54 CA143798 · United States
NCI NIH HHS · P30 CA016087-30 · United States
NCI NIH HHS · 5 P30CA16087-31 · United States
NCI NIH HHS · R01 CA133379 · United States
NCI NIH HHS · R01CA133379 · United States
NCI NIH HHS · R01 CA129831 · United States
NCI NIH HHS · 5P30CA16087-31 · United States
NCI NIH HHS · R21CA141399 · United States
NCI NIH HHS · CA129831-03S1 · United States
NCI NIH HHS · R01 CA149655 · United States
NCI NIH HHS · R01 CA105129 · United States
NCI NIH HHS · R01 CA133379-04 · United States
NCI NIH HHS · 1R01CA138234-01 · United States
NIGMS NIH HHS · R01GM088847 · United States
NCI NIH HHS · R01 CA138234 · United States
NCI NIH HHS · U54CA143798-01 · United States
NIGMS NIH HHS · R01 GM088847 · United States
NCI NIH HHS · R01 CA149655-03 · United States
Corrections
CommentIn
PMID: 21741591
CommentIn
PMID: 21779006
External Links
PubMed source DOI: 10.1016/j.ccr.2011.06.001 PMC Full Text View journal details
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