Conditional Bap1 deletion recapitulates features of MDS in mice.
Major finding: Conditional Bap1 deletion recapitulates features of MDS in mice.
Mechanism: BAP1 controls target genes by stabilizing the transcriptional regulators HCF1 and OGT.
Impact: Somatic BAP1 mutations may contribute to a subset of MDS in humans.
Germline mutations in BRCA1 associated protein-1 (BAP1), which encodes a nuclear deubiquitinase, have been linked to a uveal melanoma and mesothelioma predisposition syndrome. Somatic inactivating mutations of BAP1 also frequently occur in sporadic cases of uveal melanoma, mesothelioma, and renal cell carcinoma, and have been identified in other tumor types. To characterize the normal physiologic function of BAP1, Dey and colleagues conditionally deleted Bap1 from adult mouse tissues after observing that Bap1-null mice were embryonic lethal. Following Bap1 deletion, 100% of mice developed splenomegaly resulting from extramedullary hematopoiesis and myeloid lineage expansion. Furthermore, the peripheral blood of Bap1-deficient mice showed cytologic and morphologic features of a myelodysplastic syndrome (MDS) with similarities to human chronic myelomonocytic leukemia (CMML). The authors also generated a FLAG-BAP1 knockin mouse and identified endogenous BAP1-interacting proteins in the spleen, including the epigenetic transcriptional regulators host cell factor 1 (HCF1), O-linked N-acetylglucosamine transferase (OGT), and additional sex combs like 1 and 2 (ASXL1 and ASXL2). Of note, ASXL1 is essential for BAP1 enzymatic activity and is frequently mutated in MDS and CMML, supporting a link between BAP1 and these neoplastic diseases. BAP1 deubiquitinated and stabilized HCF1 and OGT, raising the possibility that BAP1 indirectly affects gene expression via transcriptional coregulator stabilization. Consistent with this possibility, BAP loss significantly affected the expression of a subset of genes and the vast majority of promoters occupied by BAP1 were also occupied by HCF1 and OGT. Sequencing of BAP1 in 32 patients with de novo MDS revealed that 1 patient lacking other known MDS mutations had an inactivating frameshift mutation, providing further evidence that BAP1 loss contributes to human MDS.