SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.
Humans
Histone-Lysine N-Methyltransferase
/ genetics
Apoptosis
/ genetics
Animals
Proto-Oncogene Proteins c-bcl-2
/ genetics
Mutation
Cell Line, Tumor
Drug Resistance, Neoplasm
/ genetics
Mice
Bridged Bicyclo Compounds, Heterocyclic
/ pharmacology
Sulfonamides
/ pharmacology
Lymphoma, Large B-Cell, Diffuse
/ genetics
Lymphoma, B-Cell
/ genetics
Neoplasm Proteins
/ genetics
DNA-Binding Proteins
/ genetics
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 Oct 2024
07 Oct 2024
Historique:
received:
05
07
2023
revised:
05
03
2024
accepted:
02
08
2024
medline:
5
9
2024
pubmed:
5
9
2024
entrez:
5
9
2024
Statut:
ppublish
Résumé
The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.
Identifiants
pubmed: 39235528
pii: 276954
doi: 10.1084/jem.20231143
pii:
doi:
Substances chimiques
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Proto-Oncogene Proteins c-bcl-2
0
venetoclax
N54AIC43PW
Bridged Bicyclo Compounds, Heterocyclic
0
BCL2 protein, human
0
Sulfonamides
0
KMT2D protein, human
0
Neoplasm Proteins
0
DNA-Binding Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Australian Research Council Centre of Excellence for the Mathematical Analysis of Cellular Systems
ID : CE230100001
Organisme : Leukemia and Lymphoma Society
ID : LLS SCOR 7021-20
Organisme : Sam Waxman Foundation
Organisme : Chemotherapy Foundation
Organisme : Institute for Follicular Lymphoma Innovation
Organisme : NIH HHS
ID : P50 CA217694
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA252982
Pays : United States
Organisme : Lymphoma Research Foundation
Pays : United States
Organisme : Geoffrey Beene Cancer Research Center
Organisme : Starr Cancer Consortium
ID : I10-0064
Organisme : Follicular Lymphoma Foundation
Organisme : Astrazeneca
ID : SK2021-1271
Informations de copyright
© 2024 Portelinha et al.