고명곤 (Immune Disease Institute at Harvard Medical School, 현 La Jolla Institute for Allergy and Immunology) | 한빛사논문 > 한빛사

한빛사논문, 상위피인용논문

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Immune Disease Institute at Harvard Medical School, 현 La Jolla Institute for Allergy and Immunology

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Nature, 468, 839–843 (2010) | Published online 07 November 2010 l doi:10.1038/nature09586 Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

Abstract

Myunggon Ko^1*†, Yun Huang^1*†, Anna M. Jankowska², Utz J. Pape^1,3, Mamta Tahiliani¹, Hozefa S. Bandukwala¹, Jungeun An^1†, Edward D.Lamperti¹, Kian PengKoh¹, Rebecca Ganetzky², X. Shirley Liu³, L. Aravind⁴, SuneetAgarwal⁵, JaroslawP. Maciejewski² & Anjana Rao^1†

¹Department of Pathology, Harvard Medical School, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital Boston, Boston, Massachusetts 02115, USA. ²Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, and Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, Ohio 44195, USA. ³Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA. ⁴National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. ⁵Division of Pediatric Hematology/Oncology, Children’s Hospital Boston and Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA. ^†Present address: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA (M.K., Y.H., J.A., A.R.).

*These authors contributed equally to this work.

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA^{1, 2}. 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 malignancies³. 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)^{4, 5, 6, 7, 8, 9, 10, 11, 12}. 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.

논문정보

형식Research article
게재일2010년 11월 (BRIC 등록일 )
연구진국외 연구진
분야 생명과학 > 유전학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2013-11-30)

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