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PMID: 22878500 Published · ppublish English Journal Article

Loss of the tumor suppressor BAP1 causes myeloid transformation.

Science (New York, N.Y.) ·Vol. 337 ·No. 6101 ·2012-09-21 ·Pages 1541-6

Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, Kirkpatrick DS, Pham VC, Lill JR, Bakalarski CE, Wu J, Phu L, Katavolos P, LaFave LM, Abdel-Wahab O, Modrusan Z, Seshagiri S, Dong K, Lin Z, Balazs M, Suriben R, Newton K, Hymowitz S, Garcia-Manero G, Martin F, Levine RL, Dixit VM

Abstract

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.

MeSH Terms
Animals Bone Marrow Transplantation Cell Transformation, Neoplastic Chromatin Immunoprecipitation Embryonic Development Gene Deletion Gene Expression Regulation Gene Knock-In Techniques Genes, Tumor Suppressor Hematopoiesis Host Cell Factor C1/metabolism Humans Leukemia, Myelomonocytic, Chronic/genetics,metabolism,pathology Mice Mice, Knockout Myelodysplastic Syndromes/genetics,metabolism,pathology Myeloid Cells/cytology,physiology Myeloid Progenitor Cells/cytology,physiology N-Acetylglucosaminyltransferases/metabolism Promoter Regions, Genetic Repressor Proteins/metabolism Tumor Suppressor Proteins/chemistry,genetics,metabolism Ubiquitin Thiolesterase/chemistry,genetics,metabolism
Chemicals
ASXL2 protein, mouse Asxl1 protein, mouse BAP1 protein, human BAP1 protein, mouse Hcfc1 protein, mouse Host Cell Factor C1 Repressor Proteins Tumor Suppressor Proteins N-Acetylglucosaminyltransferases Ubiquitin Thiolesterase
Authors & Affiliations
27 authors, click to expand affiliations / ORCID
Dey Anwesha
Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Seshasayee Dhaya
Noubade Rajkumar
French Dorothy M
Liu Jinfeng
Chaurushiya Mira S
Kirkpatrick Donald S
Pham Victoria C
Lill Jennie R
Bakalarski Corey E
Wu Jiansheng
Phu Lilian
Katavolos Paula
LaFave Lindsay M
Abdel-Wahab Omar
Modrusan Zora
Seshagiri Somasekar
Dong Ken
Lin Zhonghua
Balazs Mercedesz
Suriben Rowena
Newton Kim
Hymowitz Sarah
Garcia-Manero Guillermo
Martin Flavius
Levine Ross L
Dixit Vishva M
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1221711
Published
2012-09-21
Epub
2012-00-09
Pages
1541-6
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC5201002
Subset
IM
Grants
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · R01 CA173636 · United States
Corrections
CommentIn
PMID: 22997315
External Links
PubMed source DOI: 10.1126/science.1221711 PMC Full Text View journal details
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