Inactivation of BAP1 cooperates with losses of NF2 and CDKN2A to drive the development of pleural malignant mesothelioma in conditional mouse models

Pleural malignant mesothelioma is a therapy-resistant or any two of these genes, resulted in robust spheroid cancer affecting the serosal lining of the thoracic cavity. formation in vitro, suggesting that mesothelial cells from Mutations/deletions of BAP1, CDKN2A, and NF2 are the Bap1;Nf2;Cdkn2a mice have stem cell–like potential. RNA-most frequent genetic lesions in human malignant meso-seq analysis of malignant mesotheliomas from triple-CKO thelioma. We introduced various combinations of these mice revealed enrichment of genes transcriptionally regu-deletions in the pleura of conditional knockout (CKO) lated by the polycomb repressive complex 2 (PRC2) and mice, focusing on the contribution of Bap1 loss. While others previously implicated in known Bap1-related cellular homozygous CKO of Bap1, Cdkn2a, or Nf2 alone gave rise processes. These data demonstrate that somatic inactivation to few or no malignant mesotheliomas, inactivation of Bap1 of Bap1, Nf2, and Cdkn2a results in rapid, aggressive malig-cooperated with loss of either Nf2 or Cdkn2a to drive nant mesotheliomas, and that deletion of Bap1 contributes development of malignant mesothelioma in approximately to tumor development, in part, by loss of PRC2-mediated 20% of double-CKO mice, and a high incidence (22/26, repression of tumorigenic target genes and by acquisition of 85%) of malignant mesotheliomas was observed in Bap1; stem cell potential, suggesting a potential avenue for ther-Nf2;Cdkn2a (triple)-CKO mice. Malignant mesothelioma apeutic intervention. onset was rapid in triple-CKO mice, with a median survival of only 12 weeks, and malignant mesotheliomas from these Significance: Combinatorial deletions of Bap1, Nf2, and mice were consistently high-grade and invasive. Adenoviral-Cdkn2a result in aggressive mesotheliomas, with Bap1 Cre treatment of normal mesothelial cells from Bap1;Nf2; loss contributing to tumorigenesis by circumventing PRC2-Cdkn2a CKO mice, but not from mice with knockout of one mediated repression of oncogenic target genes.