Haplo-Insufficiency of BAP1 Cooperates with Inactivated TP53 in Accelerating Leukemic Transformation and Delineates a Distinct Subtype of TP53-Mutated Acute Myeloid Leukemia (AML)
Open AccessMutations in TP53 occur in ~10-15% of patients with AML and are associated with an erythroid phenotype, mutual exclusivity with recurrent drivers, and a poor prognosis. Molecular heterogeneity and the lack of a physiological relevant mouse model have resulted in a failure to understand the underlying molecular mechanisms. We discovered that loss of the histone H2A lysine 119 deubiquitinase BAP1 (BRCA1 Associated Protein 1) occurs in ~30% of patients with TP53-mutated AML and adversely impacts overall survival. While ablation of TP53 in murine HSPCs largely resulted in T-lymphoblastic lymphoma, concomitant deletion of BAP1 gave rise to an aggressive AML with full penetrance. Compound mutant mice presented with hyperleukocytosis, myeloid skewing and impaired erythroid differentiation resulting in hypercellularity, tissue infiltration and compromised survival. Bone marrow cells from these mice were able to initiate leukemia in recipient mice, which resembled acute erythroid leukemia (AEL). On the molecular level, we revealed that combined loss of BAP1 and TP53 resulted in gene expression changes subverting lineage commitment due to deregulation of Polycomb Repressor Complex 2 and changes in histone H2AK119 ubiquitination. Upregulation of erythroid transcription factor GATA1 in bone marrow cells, and infiltrating GATA1+ proerythroblasts were identified in donor mice that transplanted AEL. Thus, we establish a role for BAP1 as a haplo-insufficient tumor suppressor in TP53-mutated AML, and in addition have developed a physiological relevant murine model of AEL that can be used in future studies.
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