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.; Iorgulescu, J.B.; Zhang, W.; Notarangelo, G.; Livitz, D.; Li, S.; Davids, M.S.; Biran, A.; Fernandes, S.M.; Brown, J.R.; Lako, A.; Ciantra, Z.B.; Lawlor, M.A.; Keskin, D.B.; Udeshi, N.D.; Wierda, W.G.; Livak, K.J.; Letai, A.G.; Neuberg, D.; Harper, J.W.; Carr, S.A.; Piccioni, F.; Ott, C.J.; Leshchiner, I.; Johannessen, C.M.; Doench, J.; Mootha, V.K.; Getz, G.; Wu, C.J.

doi:10.1016/j.ccell.2019.08.005

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

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Serval ID

serval:BIB_D8662D84F281

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Cancer cell

Author(s)

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., Iorgulescu J.B., Zhang W., Notarangelo G., Livitz D., Li S., Davids M.S., Biran A., Fernandes S.M., Brown J.R., Lako A., Ciantra Z.B., Lawlor M.A., Keskin D.B., Udeshi N.D., Wierda W.G., Livak K.J., Letai A.G., Neuberg D., Harper J.W., Carr S.A., Piccioni F., Ott C.J., Leshchiner I., Johannessen C.M., Doench J., Mootha V.K., Getz G., Wu C.J.

ISSN

1878-3686 (Electronic)

ISSN-L

1535-6108

Publication state

Published

Issued date

14/10/2019

Peer-reviewed

Oui

Volume

Number

Pages

369-384.e13

Language

english

Notes

Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

Abstract

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.

Keywords

Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Apoptosis/drug effects, Apoptosis/genetics, Bridged Bicyclo Compounds, Heterocyclic/pharmacology, Bridged Bicyclo Compounds, Heterocyclic/therapeutic use, Cell Line, Tumor, Clonal Evolution/drug effects, Disease Progression, Drug Resistance, Neoplasm/drug effects, Drug Resistance, Neoplasm/genetics, Energy Metabolism/drug effects, Energy Metabolism/genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell/pathology, Male, Mice, Middle Aged, Mitochondria/drug effects, Mitochondria/pathology, Myeloid Cell Leukemia Sequence 1 Protein/metabolism, Oxidative Phosphorylation/drug effects, Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2/metabolism, Sulfonamides/pharmacology, Sulfonamides/therapeutic use, Treatment Outcome, Xenograft Model Antitumor Assays, AMPK, BCL-2, CRISPR/Cas9, chronic lymphocytic leukemia, clonal evolution, drug resistance, genome-wide screen, metabolism, mitochondrion, venetoclax

OAI-PMH

oai:serval.unil.ch:BIB_D8662D84F281

DOI

10.1016/j.ccell.2019.08.005

Pubmed

31543463

Web of science

000489949400006

Publisher's website

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

Open Access

Yes