Abstract 1541: The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation

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Abstract Introduction: Our lab discovered that mutations in the tumor suppressor BAP1 are strongly associated with metastasis and death in patients with uveal melanoma. Subsequently, other cancers have been found to harbor BAP1 mutations, including skin melanoma, kidney cancer, mesothelioma and others. Germline BAP1 mutations are responsible for a newly described genetic cancer syndrome. Therapeutic molecules that reverse the effects of BAP1 mutations could represent a potent new treatment strategy for BAP1-mutant cancers. Unfortunately, there are several obstacles to developing such therapies. First, BAP1 is a tumor suppressor that is inactivated by mutations, such that targeted therapy would need to be directed against downstream effectors that are deregulated by BAP1 loss. Second, the effectors of BAP1 that are relevant to cancer are not known. Interestingly, most known proteins that interact with Bap1 are developmental epigenetic regulators such as Asxl1/2, Cbx1/3 and Kdm1b. Third, BAP1 is difficult to study in cultured cells because BAP1 loss results in cell cycle exit and stem cell-like behavior. These obstacles led us to shift to Xenopus laevis as an in vivo developmental model to study the functions of BAP1. Results and conclusions: Loss of BAP1 during embryo development results in a failure to turn off pluripotency genes such as ventx 1, ventx2 (Xenopus orthologues of the mammal gene nanog), oct 25, oct 91 (Xenopus orthologues of the mammal gene oct3/4) and pax3, and a failure to induce lineage specification genes such as the prospective epidermis marker keratin1 and the melanocyte precursor marker sox10. This block in the shift from pluripotency to differentiation programs results in a delay in gastrulation, neural crest specification and migration, mesodermal differentiation and other phenotypes. The BAP1-deficient phenotype can be rescued by Xenopus or human wildtype BAP1 or by the histone deacetylase inhibitor SAHA (vorinostat). We conclude that BAP1 is a fundamental regulator of multiple developmental lineages, including the neural crest from which melanomas arises, and that this in vivo model can be used to screen for novel therapeutic compounds that reverse the phenotypic effects of BAP1 loss. Citation Format: Jeffim N. Kuznetsov, Tristan Aguero, Stefan Kurtenbach, Matthew G. Field, Mary Lou King, J William Harbour. The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1541. doi:10.1158/1538-7445.AM2017-1541