Publication Date:
2010-11-09
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003755/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003755/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ko, Myunggon -- Huang, Yun -- Jankowska, Anna M -- Pape, Utz J -- Tahiliani, Mamta -- Bandukwala, Hozefa S -- An, Jungeun -- Lamperti, Edward D -- Koh, Kian Peng -- Ganetzky, Rebecca -- Liu, X Shirley -- Aravind, L -- Agarwal, Suneet -- Maciejewski, Jaroslaw P -- Rao, Anjana -- 1 UL1 RR 025758-02/RR/NCRR NIH HHS/ -- K08 HL089150/HL/NHLBI NIH HHS/ -- K24 HL077522/HL/NHLBI NIH HHS/ -- R01 AI044432/AI/NIAID NIH HHS/ -- R01 AI044432-12/AI/NIAID NIH HHS/ -- R01 AI044432-13/AI/NIAID NIH HHS/ -- R01 AI44432/AI/NIAID NIH HHS/ -- R01 HD065812/HD/NICHD NIH HHS/ -- R01 HG4069/HG/NHGRI NIH HHS/ -- R01 HL098522/HL/NHLBI NIH HHS/ -- R37 CA042471/CA/NCI NIH HHS/ -- R37 CA042471-20/CA/NCI NIH HHS/ -- R37 CA042471-21/CA/NCI NIH HHS/ -- RC1 DA028422/DA/NIDA NIH HHS/ -- RC1 DA028422-01/DA/NIDA NIH HHS/ -- RC1 DA028422-02/DA/NIDA NIH HHS/ -- UL1 RR025758/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Dec 9;468(7325):839-43. doi: 10.1038/nature09586.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21057493" target="_blank"〉PubMed〈/a〉
Keywords:
5-Methylcytosine/*metabolism
;
Animals
;
Biocatalysis
;
Cell Differentiation
;
Cell Line
;
CpG Islands/genetics
;
DNA Methylation
;
DNA, Neoplasm/chemistry/metabolism
;
DNA-Binding Proteins/genetics/*metabolism
;
Humans
;
*Hydroxylation
;
Leukemia, Myeloid, Acute/genetics/*metabolism/pathology
;
Mice
;
Mice, Inbred C57BL
;
Mutant Proteins/genetics/*metabolism
;
Mutation
;
Myelodysplastic Syndromes/genetics/*metabolism/pathology
;
Proto-Oncogene Proteins/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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