Oral Presentation 25th Lorne Cancer Conference 2013

Tumor Suppressor role for the deubiquitinase, BAP1 (#29)

Vishva Dixit 1
  1. Research Genentech, Inc., South San Francisco, CA, United States

Deubiquitinating enzyme BAP1 (BRCA1-associated protein is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. While the Drosophila ortholog Calypso deubiquitinates histone H2A as part of the polycomb complex that represses transcription of developmental regulators, only mammalian BAP1 has the binding motif that engages the transcriptional co-factor HCF-1 (Host Cell Factor 1)  and therefore might form additional complexes.  Here we use knock-in mice expressing BAP1 with a C-terminal 3xFlag epitope tag and mass spectrometry to define the endogenous BAP1 interactome in various tissues.  We also investigate the normal physiological role of BAP1 using Bap1-deficient mice.  Bap1 gene deletion was lethal during embryo development, but systemic deletion in adult mice caused splenomegaly and many of the features of human myelodysplastic syndrome (MDS), including neutrophilia, monocytosis, thrombocytopenia, anemia, and an expanded hematopoietic stem cell-enriched lineage- ScaI+ Kit+ (LSK) population.  Subsequent sequence analysis of bone marrow aspirates from de novo human MDS patients identified a novel somatic,  mutation in Bap1 within the catalytic domain, implying that Bap1 loss of function has similar consequences in mouse and man.  By comparing ChIP-sequencing data, obtained using BAP1.3xFlag KI cells to map BAP1 complex binding sites, and RNA sequencing data that identified genes dysregulated in BAP1-deficient cells, we identified a list of potentially critical BAP1-regulated genes that included the Il7r gene, a known regulator of hematopoietic cell survival that is decreased in clinical MDS samples.