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Cancer Cell DOI:10.1016/j.ccell.2019.08.005

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

Publication TypeJournal Article
Year of Publication2019
AuthorsGuièze, R, Liu, VM, Rosebrock, D, Jourdain, AA, Hernández-Sánchez, M, Zurita, AMartinez, Sun, J, Hacken, ETen, Baranowski, K, Thompson, PA, Heo, J-M, Cartun, Z, Aygun, O, J Iorgulescu, B, Zhang, W, Notarangelo, G, Livitz, D, Li, S, Davids, MS, Biran, A, Fernandes, SM, Brown, JR, Lako, A, Ciantra, ZB, Lawlor, MA, Keskin, DB, Udeshi, ND, Wierda, WG, Livak, KJ, Letai, AG, Neuberg, D, J Harper, W, Carr, SA, Piccioni, F, Ott, CJ, Leshchiner, I, Johannessen, CM, Doench, J, Mootha, VK, Getz, G, Wu, CJ
JournalCancer Cell
Date Published2019 Sep 04

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.


Alternate JournalCancer Cell
PubMed ID31543463