@article{db641356869645aaab935b7bd9f05562,
title = "DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia",
abstract = "Somatic mutations in IDH1/IDH2 and TET2 result in impaired TET2-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The observation that WT1 inactivating mutations anticorrelate with TET2/IDH1/IDH2 mutations in acute myeloid leukemia (AML) led us to hypothesize that WT1 mutations may impact TET2 function. WT1 mutant AML patients have reduced 5hmC levels similar to TET2/IDH1/IDH2 mutant AML. These mutations are characterized by convergent, site-specific alterations in DNA hydroxymethylation, which drive differential gene expression more than alterations inDNA promoter methylation. WT1 overexpression increases global levels of 5hmC, and WT1 silencing reduced 5hmC levels. WT1 physically interacts with TET2 and TET3, and WT1 loss of function results in a similar hematopoietic differentiation phenotype as observed with TET2 deficiency. These data provide a role for WT1 in regulating DNA hydroxymethylation and suggest that TET2 IDH1/IDH2 and WT1 mutations define an AML subtype defined by dysregulated DNA hydroxymethylation. Mutational studies in patients with acute myeloid leukemia (AML) have identified recurrent mutations in TET2 and IDH1/IDH2, and these mutations result in a reduction in 5-hydroxymethylcytosine (5hmC) levels. Rampal etal. demonstrate that WT1 mutations anticorrelate with TET2 and IDH1/IDH2 mutations, and WT1 mutant AMLs have decreased 5hmC levels, consistent with reduced TET2 function.",
author = "Raajit Rampal and Altuna Alkalin and Jozef Madzo and Aparna Vasanthakumar and Elodie Pronier and Jay Patel and Yushan Li and Jihae Ahn and Omar Abdel-Wahab and Alan Shih and Chao Lu and Ward, {Patrick S.} and Tsai, {Jennifer J.} and Todd Hricik and Valeria Tosello and Tallman, {Jacob E.} and Xinyang Zhao and Danette Daniels and Qing Dai and Luisa Ciminio and Iannis Aifantis and Chuan He and Francois Fuks and Tallman, {Martin S.} and Adolfo Ferrando and Stephen Nimer and Elisabeth Paietta and Thompson, {Craig B.} and Licht, {Jonathan D.} and Mason, {Christopher E.} and Godley, {Lucy A.} and Ari Melnick and Figueroa, {Maria E.} and Levine, {Ross L.}",
note = "Funding Information: This work was supported by a grant from the National Cancer Institute Physical Sciences Oncology Center (U54CA143798-01) to R.L.L., A.M., and J.D.L., a Leukemia and Lymphoma Society Specialized Center of Research (LLS SCOR) grant to S.D.N., an LLS SCOR to J.D.L. and A.M., a grant from the Gabrielle{\textquoteright}s Angel Fund to R.L.L., C.H., and A.M.M., grant CA172636-01 to R.L.L., I.A., and A.M., and grants CA129831 and CA129831-03S1 to L.A.G. A.V. is supported by an NIH F32 award. C.E.M. and A.A. are supported by R01HG006798, R01NS076465. M.E.F. is supported by a Leukemia and Lymphoma Society Special Fellow award and a Doris Duke Charitable Foundation Clinical Scientist Development award. O.A.-W. is an American Society of Hematology Basic Research Fellow. A.M. is a Burroughs Wellcome Clinical Translational Scholar. A.M. also is also supported by the Sackler Center for Biomedical and Physical Sciences. R.L.L. and A.F. are funded by Leukemia and Lymphoma Society Scholar Awards. R.R. is an American Society of Hematology Basic Research Fellow. We thank Vicki Huff for kindly providing WT1 truncation constructs. Publisher Copyright: {\textcopyright} 2014 The Authors.",
year = "2014",
month = dec,
day = "11",
doi = "10.1016/j.celrep.2014.11.004",
language = "English (US)",
volume = "9",
pages = "1841--1855",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}