Loss of the Tumor Suppressor BAP1 Causes Myeloid Transformation

被引：335

作者：

Dey, Anwesha ^{[1
]}

Seshasayee, Dhaya ^{[2
]}

Noubade, Rajkumar ^{[2
]}

French, Dorothy M. ^{[3
]}

Liu, Jinfeng ^{[4
]}

Chaurushiya, Mira S. ^{[1
]}

Kirkpatrick, Donald S. ^{[5
]}

Pham, Victoria C. ^{[5
]}

Lill, Jennie R. ^{[5
]}

Bakalarski, Corey E. ^{[4
]}

Wu, Jiansheng ^{[5
]}

Phu, Lilian ^{[5
]}

Katavolos, Paula ^{[6
]}

LaFave, Lindsay M. ^{[7
,8
]}

Abdel-Wahab, Omar ^{[7
,8
]}

Modrusan, Zora ^{[9
]}

Seshagiri, Somasekar ^{[9
]}

Dong, Ken ^{[10
]}

Lin, Zhonghua ^{[11
]}

Balazs, Mercedesz ^{[11
]}

Suriben, Rowena ^{[1
]}

Newton, Kim ^{[1
]}

Hymowitz, Sarah ^{[10
]}

Garcia-Manero, Guillermo ^{[12
]}

Martin, Flavius ^{[2
]}

Levine, Ross L. ^{[7
,8
]}

Dixit, Vishva M. ^{[1
]}

机构：

[1] Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Safety Assessment, San Francisco, CA 94080 USA

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

[8] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA

[9] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[10] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[11] Genentech Inc, Dept Translat Immunol, San Francisco, CA 94080 USA

[12] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

来源：

SCIENCE | 2012年 / 337卷 / 6101期

关键词：

MYELODYSPLASTIC SYNDROMES; UBIQUITIN HYDROLASE; GENE-EXPRESSION; MUTATIONS; MOUSE; PREDISPOSE; LEUKEMIA; ASXL1;

D O I：

10.1126/science.1221711

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor-1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans.

引用

页码：1541 / 1546

页数：6

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