NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death Journal Article


Authors: Liu, Y.; Mondello, P.; Erazo, T.; Tannan, N. B.; Asgari, Z.; de Stanchina, E.; Nanjangud, G.; Seshan, V. E.; Wang, S.; Wendel, H. G.; Younes, A.
Article Title: NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death
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. © 2018 National Academy of Sciences. All Rights Reserved.
Keywords: apoptosis; bcl2; lymphoma; bim; noxa
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 115
Issue: 47
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2018-11-20
Start Page: 12034
End Page: 12039
Language: English
DOI: 10.1073/pnas.1806928115
PUBMED: 30404918
PROVIDER: scopus
PMCID: PMC6255185
DOI/URL:
Notes: Article -- Export Date: 3 December 2018 -- Source: Scopus
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MSK Authors
  1. Venkatraman Ennapadam Seshan
    282 Seshan
  2. Hans Guido Wendel
    58 Wendel
  3. Zahra Asgari
    6 Asgari
  4. Shenqiu Wang
    4 Wang
  5. Anas Younes
    187 Younes
  6. Yuxuan Liu
    3 Liu
  7. Neeta Bala
    1 Bala