Venetoclax sensitivity in multiple myeloma is associated with B-cell gene expression.
B-Lymphocytes
/ metabolism
Basic-Leucine Zipper Transcription Factors
/ genetics
Bridged Bicyclo Compounds, Heterocyclic
/ pharmacology
Cell Line, Tumor
Chromosomes, Human, Pair 11
/ genetics
Chromosomes, Human, Pair 14
/ genetics
Cyclin D1
/ genetics
Epigenesis, Genetic
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Gene Knockdown Techniques
Humans
Multiple Myeloma
/ drug therapy
Proto-Oncogene Proteins c-bcl-2
/ genetics
Sulfonamides
/ pharmacology
Translocation, Genetic
/ drug effects
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
01 07 2021
01 07 2021
Historique:
received:
26
06
2020
accepted:
29
01
2021
pubmed:
3
3
2021
medline:
15
12
2021
entrez:
2
3
2021
Statut:
ppublish
Résumé
Venetoclax is a highly potent, selective BCL2 inhibitor capable of inducing apoptosis in cells dependent on BCL2 for survival. Most myeloma is MCL1-dependent; however, a subset of myeloma enriched for translocation t(11;14) is codependent on BCL2 and thus sensitive to venetoclax. The biology underlying this heterogeneity remains poorly understood. We show that knockdown of cyclin D1 does not induce resistance to venetoclax, arguing against a direct role for cyclin D1 in venetoclax sensitivity. To identify other factors contributing to venetoclax response, we studied a panel of 31 myeloma cell lines and 25 patient samples tested for venetoclax sensitivity. In cell lines, we corroborated our previous observation that BIM binding to BCL2 correlates with venetoclax response and further showed that knockout of BIM results in decreased venetoclax sensitivity. RNA-sequencing analysis identified expression of B-cell genes as enriched in venetoclax-sensitive myeloma, although no single gene consistently delineated sensitive and resistant cells. However, a panel of cell surface makers correlated well with ex vivo prediction of venetoclax response in 21 patient samples and may serve as a biomarker independent of t(11;14). Assay for transposase-accessible chromatin sequencing of myeloma cell lines also identified an epigenetic program in venetoclax-sensitive cells that was more similar to B cells than that of venetoclax-resistant cells, as well as enrichment for basic leucine zipper domain-binding motifs such as BATF. Together, these data indicate that remnants of B-cell biology are associated with BCL2 dependency and point to novel biomarkers of venetoclax-sensitive myeloma independent of t(11;14).
Identifiants
pubmed: 33649772
pii: S0006-4971(21)00508-5
doi: 10.1182/blood.2020007899
pmc: PMC8462405
doi:
Substances chimiques
BATF protein, human
0
BCL2 protein, human
0
Basic-Leucine Zipper Transcription Factors
0
Bridged Bicyclo Compounds, Heterocyclic
0
CCND1 protein, human
0
Proto-Oncogene Proteins c-bcl-2
0
Sulfonamides
0
Cyclin D1
136601-57-5
venetoclax
N54AIC43PW
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3604-3615Subventions
Organisme : NCI NIH HHS
ID : P30 CA138292
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192844
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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