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

Guièze, R., Liu, V. M., Rosebrock, D., Jourdain, A. A., Hernández-Sánchez, M., Martinez Zurita, A., Sun, J., Ten Hacken, E., Baranowski, K., Thompson, P. A., Heo, J. M., Cartun, Z., Aygün, O., Iorgulescu1, J. B., Zhang, W., Notarangelo, G., Livitz, D., Li, S., Davids, M. S., . . . Wu, C. J. (2019). Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid Malignancies. Cancer Cell, 36(4), 369–384. https://doi.org/10.1016/j.ccell.2019.08.005

Resumen

[EN]Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDAapproved 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.

URI

http://hdl.handle.net/10366/146272

ISSN

1535-6108

DOI

10.1016/j.ccell.2019.08.005

Versión del editor

https://doi.org/10.1016/j.ccell.2019.08.005

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