Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia

被引：419

作者：

Ntziachristos, Panagiotis ^{[1
,2
,3
,4
]}

Tsirigos, Aristotelis ^{[5
]}

Van Vlierberghe, Pieter ^{[6
,7
,8
]}

Nedjic, Jelena ^{[1
,2
,3
,4
]}

Trimarchi, Thomas ^{[1
,2
,3
,4
]}

Flaherty, Maria Sol ^{[6
]}

Ferres-Marco, Dolors ^{[9
]}

da Ros, Vanina ^{[9
]}

Tang, Zuojian ^{[10
,11
]}

Siegle, Jasmin ^{[1
,2
,3
,4
]}

Asp, Patrik ^{[3
,4
]}

Hadler, Michael ^{[6
]}

Rigo, Isaura ^{[6
]}

De Keersmaecker, Kim ^{[12
,13
]}

Patel, Jay ^{[14
,15
]}

Tien Huynh ^{[5
]}

Utro, Filippo ^{[5
]}

Poglio, Sandrine ^{[16
,17
,18
,19
]}

Samon, Jeremy B. ^{[6
,7
,8
]}

Paietta, Elisabeth ^{[20
]}

Racevskis, Janis ^{[20
]}

Rowe, Jacob M. ^{[21
]}

Rabadan, Raul ^{[22
]}

Levine, Ross L. ^{[14
,15
]}

Brown, Stuart ^{[10
,11
]}

Pflumio, Francoise ^{[16
,17
,18
,19
]}

Dominguez, Maria ^{[9
]}

Ferrando, Adolfo ^{[6
,7
,8
]}

Aifantis, Iannis ^{[1
,2
,3
,4
]}

机构：

[1] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10003 USA

[2] NYU, Sch Med, Dept Pathol, New York, NY USA

[3] NYU, Sch Med, Inst Canc, New York, NY USA

[4] NYU, Sch Med, Helen L & Martin S Kimmel Ctr Stem Cell Biol, New York, NY USA

[5] IBM Thomas J Watson Res Ctr, Computat Biol Ctr, Yorktown Hts, NY USA

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

[7] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA

[8] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA

[9] Univ Miguel Hernandez, Inst Neurociencias Alicante, Consejo Super Invest Cient, Alicante, Spain

[10] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA

[11] NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY USA

[12] Flanders Inst Biotechnol, Dept Mol & Dev Genet, Louvain, Belgium

[13] Catholic Univ Louvain, Ctr Human Genet, B-3000 Louvain, Belgium

[14] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[15] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA

[16] Inst Radiobiol Cellulaire & Mol, CEA, Unite Mixte Rech 967, Fontenay Aux Roses, France

[17] INSERM, U967, Fontenay Aux Roses, France

[18] Univ Paris Diderot, UMR 967, Fontenay Aux Roses, France

[19] Univ Paris Sud, UMR 967, Fontenay Aux Roses, France

[20] Montefiore Med Ctr N, Bronx, NY USA

[21] Rambam Med Ctr, Haifa, Israel

[22] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USA

来源：

NATURE MEDICINE | 2012年 / 18卷 / 02期

基金：

美国国家卫生研究院;

关键词：

SOMATIC MUTATIONS; NOTCH1; PRC2; EZH2; CONTEXT;

D O I：

10.1038/nm.2651

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling(1). In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2)(2,3), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3)(4) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

引用

页码：298 / 303

页数：6

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