Emerging Anatomy of the BAP1 Tumor Suppressor System

The genetic drivers of cancer are incredibly complex; they include frequent mutations in a small number of tumor suppressors and oncogenes, as well as a large landscape of rare genetic variants that may promote tumorigenesis in a lineage-dependent manner. A recent flurry of papers has demonstrated prevalent somatic and germline mutations in a novel tumor suppressor, the deubiquitinating enzyme BAP1, in a variety of tumor types, including some with metastatic potential ( 1 – 5 ). Through analysis of mice lacking BAP1 and human tumors, Dey et al. now identify BAP1 as a tumor suppressor in myelodysplastic syndrome (MDS), a bone marrow and blood cell cancer syndrome that often evolves into highly aggressive acute myelogenous leukemia (AML), as reported on page 1541 of this issue ( 6 ). Functional analysis of the BAP1 protein interaction network in vivo, together with target gene identification, revealed a transcription complex in which ubiquitin removal from regulatory components by BAP1 likely specifies the repertoire of genes underlying tumor suppression.