Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies
Copyright © 2019 Elsevier Inc. All rights reserved..
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.
| Errataetall: |
CommentIn: Cancer Cell. 2019 Oct 14;36(4):341-343. - PMID 31614111 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Cancer cell - 36(2019), 4 vom: 14. Okt., Seite 369-384.e13 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Guièze, Romain [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.05.2020 Date Revised 21.04.2021 published: Print-Electronic CommentIn: Cancer Cell. 2019 Oct 14;36(4):341-343. - PMID 31614111 Citation Status MEDLINE |
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| doi: |
10.1016/j.ccell.2019.08.005 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM301514356 |
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| 500 | |a CommentIn: Cancer Cell. 2019 Oct 14;36(4):341-343. - PMID 31614111 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AMPK | |
| 650 | 4 | |a BCL-2 | |
| 650 | 4 | |a CRISPR/Cas9 | |
| 650 | 4 | |a chronic lymphocytic leukemia | |
| 650 | 4 | |a clonal evolution | |
| 650 | 4 | |a drug resistance | |
| 650 | 4 | |a genome-wide screen | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a mitochondrion | |
| 650 | 4 | |a venetoclax | |
| 650 | 7 | |a BCL2 protein, human |2 NLM | |
| 650 | 7 | |a Bridged Bicyclo Compounds, Heterocyclic |2 NLM | |
| 650 | 7 | |a MCL1 protein, human |2 NLM | |
| 650 | 7 | |a Myeloid Cell Leukemia Sequence 1 Protein |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-bcl-2 |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
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