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Loss of the tumor suppressor BAP1 causes myeloid transformation.

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.

Pubmed ID: 22878500

Authors

  • 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

Journal

Science (New York, N.Y.)

Publication Data

September 21, 2012

Associated Grants

None

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
  • Humans
  • Leukemia, Myelomonocytic, Chronic
  • Mice
  • Mice, Knockout
  • Myelodysplastic Syndromes
  • Myeloid Cells
  • Myeloid Progenitor Cells
  • N-Acetylglucosaminyltransferases
  • Promoter Regions, Genetic
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase