Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors.

Mutations in TP53 are mutually exclusive with other known drivers of myeloid transformation and define a distinct molecular subtype within de novo acute myeloid leukemia (AML) that is associated with a complex karyotype, resistance to chemotherapy, and poor prognosis. Although TP53 defects are rare in de novo AML, biallelic mutations are a defining molecular feature of erythroleukemia. The genetic alterations that cooperate with defective TP53 to transform erythroid progenitors remain unknown. We found that loss of BAP1 (BRCA1-associated protein 1) co-occurs in one-third of patients with TP53-mutated AML, is associated with an erythroid-primed gene expression signature, and confers an additional adverse effect on overall survival. BAP1 is a tumor suppressor involved in the DNA damage response as well as epigenetic regulation through histone H2AK119 deubiquitination. Although Bap1KO mice develop myelodysplasia with prominent dyserythropoiesis, combined deletion of Bap1 and Trp53 caused transplantable erythroleukemia, and occasionally mixed AML, mirroring the heterogeneity of human disease. Bulk and single-cell RNA sequencing coupled to chromatin immunoprecipitation sequencing in hematopoietic progenitors revealed that Bap1 loss triggers a proinflammatory response and cooperates with Trp53 deficiency to transform erythroid-primed multipotent progenitors. Mechanistically, genomic instability led to the development of erythroleukemia, whereas epigenetic deregulation caused myelomonocytic skewing suggesting a dichotomous and context dependent role for BAP1. We also demonstrate that BAP1-deficient erythroleukemia is dependent on BCL2L1 expression and is sensitive to B-cell lymphoma-extra large inhibitors in vivo.