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NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Nov 20; Vol. 115 (47), pp. 12034-12039. Date of Electronic Publication: 2018 Nov 07. - Publication Year :
- 2018
-
Abstract
- Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL.<br />Competing Interests: Conflict of interest statement: A.Y. has potential conflicts of interest; funds for research came from Servier and for clinical trials from Servier and Novartis.<br /> (Copyright © 2018 the Author(s). Published by PNAS.)
- Subjects :
- Animals
Apoptosis drug effects
Apoptosis Regulatory Proteins metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Female
Gene Amplification drug effects
Histone Deacetylase Inhibitors pharmacology
Histone Deacetylase Inhibitors therapeutic use
Humans
Lymphoma, Large B-Cell, Diffuse metabolism
Lymphoma, Large B-Cell, Diffuse pathology
Mice
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Panobinostat pharmacology
Proto-Oncogene Proteins c-bcl-2 metabolism
Xenograft Model Antitumor Assays
Lymphoma, Large B-Cell, Diffuse drug therapy
Lymphoma, Large B-Cell, Diffuse genetics
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 47
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 30404918
- Full Text :
- https://doi.org/10.1073/pnas.1806928115