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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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Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

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Title
Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2
Author
Ko, Myung GonHuang, YunJankowska, Anna MPape, Utz JTahiliani, MamtaBandukwala, Hozefa SAn, JungeunLamperti, Edward DKoh, Kian PengGanetzky, RebeccaLiu, X ShirleyAravind, LAgarwal, SuneetMaciejewski, Jaroslaw PRao, Anjana
Keywords
DNA METHYLATION; MUTATIONS; MALIGNANCIES; THERAPY; COMMON; HYPOMETHYLATION; MYELOFIBROSIS; EPIGENETICS; CONVERSION; NEOPLASMS
Issue Date
2010-12
Publisher
NATURE PUBLISHING GROUP
Citation
NATURE, v.468, no.7325, pp.839 - 843
Abstract
TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. © 2010 Macmillan Publishers Limited. All rights reserved.
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DOI
10.1038/nature09586
ISSN
0028-0836
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PHY_Journal Papers
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