Journal
BLOOD
Volume 118, Issue 9, Pages 2551-2555Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-12-324707
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Funding
- MPN research foundation
- Fondation de France
- Institut National du Cancer
- Canceropole Ile de France (Cancer Stem Cell network)
- Agence Nationale pour la Recherche (ANR)
- Ligue Nationale Contre le Cancer
- National Institute of Health [CA129831, CA129831-03S1]
- Ministere de la Recherche MNERT
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TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid malignancies, including myeloproliferative neoplasms. Here we show that the level of 5-hmC is decreased in granulocyte DNA from myeloproliferative neoplasm patients with TET2 mutations compared with granulocyte DNA from healthy patients. Inhibition of TET2 by RNA interference decreases 5-hmC levels in both human leukemia cell lines and cord blood CD34(+) cells. These results confirm the enzymatic function of TET2 in human hematopoietic cells. Knockdown of TET2 in cord blood CD34(+) cells skews progenitor differentiation toward the granulomonocytic lineage at the expense of lymphoid and erythroid lineages. In addition, by monitoring in vitro granulomonocytic development we found a decreased granulocytic differentiation and an increase in monocytic cells. Our results indicate that TET2 disruption affects 5-hmC levels in human myeloid cells and participates in the pathogenesis of myeloid malignancies through the disturbance of myeloid differentiation. (Blood.2011;118(9):2551-2555)
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