title: Loss of the tumor suppressor BAP1 causes myeloid transformation.
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.
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Anwesha
authors.initials: A
authors.lastname: Dey
authors.forename: Dhaya
authors.initials: D
authors.lastname: Seshasayee
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Noubade
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Mira S
authors.initials: MS
authors.lastname: Chaurushiya
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Pham
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
authors.forename: Corey E
authors.initials: CE
authors.lastname: Bakalarski
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: Lilian
authors.initials: L
authors.lastname: Phu
authors.forename: Paula
authors.initials: P
authors.lastname: Katavolos
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: LaFave
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Ken
authors.initials: K
authors.lastname: Dong
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.forename: Rowena
authors.initials: R
authors.lastname: Suriben
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.forename: Sarah
authors.initials: S
authors.lastname: Hymowitz
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D047108:Embryonic Development; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D016147:Genes, Tumor Suppressor; D006410:Hematopoiesis; D051863:Host Cell Factor C1 / Q000378:metabolism; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000166:cytology / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000502:physiology; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C484296:ASXL2 protein, mouse; C510915:Asxl1 protein, mouse; C400134:BAP1 protein, human; C575444:BAP1 protein, mouse; C497693:Hcfc1 protein, mouse; D051863:Host Cell Factor C1; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D017351:N-Acetylglucosaminyltransferases; D043222:Ubiquitin Thiolesterase