ABSTRACT: Guieze R, Liu VM, Rosebrock D, Jourdain AA, Hernandez-Sanchez M, Martinez A, Sun J, Baranowski K, Thompson PA, Heo J, Cartun Z, Aygun O, Notarangelo G, Livitz D, Li S, Hacken ET, Davids MS, Iorgelescu JB, Zhang W, Biran A, Fernandes SM, Brown JR, Ana Lako A, Ciantra ZB, Keskin DB, Udeshi ND, Wierda WG, Livak KJ, Letai AG, Neuberg D, Harper JW, Carr SA, Piccioni F, Ott CJ, Leshchiner I, Johannessen CM, Doench J, Mootha VK, Getz G, Wu CJ. 2019. Mitochondrial apoptosis can now be targeted in lymphoid malignancies with the first FDA-approved B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that resistance to venetoclax in patients with chronic lymphocytic leukemia is associated with marked and 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. Systematic analyses of patient samples and cell lines confirmed MCL-1 overexpression and AMPK activation as underlying mechanisms for venetoclax resistance. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.
Steven A. Carr 
