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Ko, Myunggon
Molecular Immunology & Cancer Epigenetics
Research Interests
  • TET proteins, DNA hydroxymethylation, oncogenesis, cancer stem cells, cancer therapy

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Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice

Cited 140 times inthomson ciCited 128 times inthomson ci
Title
Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice
Author
Ko, Myung GonBandukwala, Hozefa SAn, JungeunLamperti, Edward DThompson, Elizabeth CHastie, RyanTsangaratou, AngelikiRajewsky, KlausKoralov, Sergei BRao, Anjana
Issue Date
2011-08
Publisher
NATL ACAD SCIENCES
Citation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.108, no.35, pp.14566 - 14571
Abstract
The Ten-Eleven-Translocation 2 (TET2) gene encodes a member of TET family enzymes that alters the epigenetic status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies, including myelodysplastic syndromes, myeloproliferative neoplasms, and chronic myelomonocytic leukemia. By analyzing mice with targeted disruption of the Tet2 catalytic domain, we show here that Tet2 is a critical regulator of self-renewal and differentiation of hematopoietic stem cells (HSCs). Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner. In competitive transplantation assays, Tet2-deficient HSCs were capable of multi-lineage reconstitution and possessed a competitive advantage over wild-type HSCs, resulting in enhanced hematopoiesis into both lymphoid and myeloid lineages. In vitro, Tet2 deficiency delayed HSC differentiation and skewed development toward the monocyte/macrophage lineage. Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs.
URI
https://scholarworks.unist.ac.kr/handle/201301/12566
URL
http://www.pnas.org/content/108/35/14566.short
DOI
10.1073/pnas.1112317108
ISSN
0027-8424
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