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Title

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

AuthorsGuièze, Romain; Liu, Vivian M.; Rosebrock, Daniel; Jourdain, Alexis A.; Hernández-Sánchez, María; Martinez Zurita, Aina; Sun, Jing; Ten Hacken, Elisa; Baranowski, Kaitlyn; Thompson, Philip A.; Heo, Jin-Mi; Cartun, Zachary; Aygün, Ozan; Iorgulescu, J. Bryan; Zhang, Wandi; Notarangelo, Giulia; Livitz, Dimitri; Li, Shuqiang; Davids, Matthew S.; Biran, Anat; Fernandes, Stacey M.; Brown, Jennifer R.; Lako, Ana; Ciantra, Zoe B.; Lawlor, Matthew A.; Keskin, Derin B.; Udeshi, Namrata D.; Wierda, William G.; Livak, Kenneth J.; Letai, Anthony G.; Neuberg, Donna; Wade Harper, J.; Carr, Steven A.; Piccioni, Federica; Ott, Christopher J.; Leshchiner, Ignaty; Johannessen, Cory M.; Doench, John; Mootha, Vamsi K.; Getz, Gad; Wu, Catherine J.
KeywordsBCL-2
Venetoclax
Chronic lymphocytic leukemia
Drug resistance
Genome-wide screen
CRISPR/Cas9
Clonal evolution
Mitochondrion
Metabolism
AMPK
Issue Date14-Oct-2019
PublisherElsevier
CitationCancer Cell 36(4): 369-384.e13 (2019)
AbstractMitochondrial 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.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.
Publisher version (URL)http://dx.doi.org/10.1016/j.ccell.2019.08.005
URIhttp://hdl.handle.net/10261/209826
DOI10.1016/j.ccell.2019.08.005
ISSN1535-6108
E-ISSN1878-3686
Appears in Collections:(IBMCC) Artículos
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