Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance. [Display omitted] •B-lymphoid cancer cells can escape to venetoclax by overexpressing MCL-1•Modulation of AMPK/PKA axis and lymphoid transcription drive venetoclax resistance•Venetoclax resistance involves changes in cellular energy metabolism such as OXPHOS•Metabolic modulators can cooperate with venetoclax to overcome resistance Guièze et al. show that resistance to the BCL-2 inhibitor venetoclax in chronic lymphocytic leukemia is associated with complex clonal shifts and identify, in addition to the known involvement by BCL-2 family members, regulators of lymphoid transcription and cellular energy metabolism as resistance drivers.