DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia

被引：220

作者：

Rampal, Raajit ^{[1
,2
]}

Alkalin, Altuna ^{[17
,20
]}

Madzo, Jozef ^{[3
]}

Vasanthakumar, Aparna ^{[3
]}

Pronier, Elodie ^{[1
]}

Patel, Jay ^{[1
]}

Li, Yushan ^{[4
]}

Ahn, Jihae ^{[1
]}

Abdel-Wahab, Omar ^{[1
,2
]}

Shih, Alan ^{[1
,2
]}

Lu, Chao ^{[5
]}

Ward, Patrick S.

Tsai, Jennifer J. ^{[15
]}

Hricik, Todd ^{[1
]}

Tosello, Valeria ^{[6
]}

Tallman, Jacob E. ^{[1
]}

Zhao, Xinyang ^{[7
]}

Daniels, Danette ^{[18
]}

Dai, Qing ^{[8
,9
]}

Ciminio, Luisa ^{[10
]}

Aifantis, Iannis ^{[10
]}

He, Chuan ^{[8
,9
]}

Fuks, Francois ^{[16
]}

Tallman, Martin S. ^{[2
]}

Ferrando, Adolfo ^{[6
]}

Nimer, Stephen ^{[12
]}

Paietta, Elisabeth ^{[11
]}

Thompson, Craig B. ^{[5
]}

Licht, Jonathan D. ^{[13
]}

Mason, Christopher E. ^{[17
,21
,22
]}

Godley, Lucy A. ^{[3
,14
]}

Melnick, Ari ^{[4
]}

Figueroa, Maria E. ^{[4
,19
]}

Levine, Ross L. ^{[1
,2
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10065 USA

[3] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA

[4] Weill Cornell Med Coll, Dept Hematol Oncol, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[6] Columbia Univ, Med Ctr, Inst Canc Genet, New York, NY 10032 USA

[7] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[8] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[9] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[10] NYU, Dept Phys, Inst Canc, New York, NY 10016 USA

[11] Montefiore Med Ctr, New York, NY 10466 USA

[12] Sylvester Comprehens Canc Ctr, Dept Med, Miami, FL 33136 USA

[13] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[14] Univ Chicago, Comprehens Canc Res Ctr, Chicago, IL 60637 USA

[15] Weill Cornell Grad Sch Med Sci, Dept Immunol & Microbial Pathogenesis, New York, NY 10065 USA

[16] Univ Libre Bruxelles, Fac Med, Lab Canc Epigenet, B-1070 Brussels, Belgium

[17] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA

[18] Promega Corp, Madison, WI 53703 USA

[19] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[20] Berlin Inst Med Syst Biol, Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany

[21] HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA

[22] Feil Family Brain & Mind Res Inst, Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA

来源：

CELL REPORTS | 2014年 / 9卷 / 05期

关键词：

WILMS-TUMOR GENE; THERAPEUTIC TARGET; STEM-CELLS; 5-HYDROXYMETHYLCYTOSINE; EXPRESSION; BINDING; MOUSE; MICE; DIFFERENTIATION; LYMPHOMAGENESIS;

D O I：

10.1016/j.celrep.2014.11.004

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 in DNA 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.

引用

页码：1841 / 1855

页数：15

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