Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma.
Acetyltransferases
/ genetics
Animals
B-Lymphocytes
/ physiology
CREB-Binding Protein
/ genetics
Cell Line
E1A-Associated p300 Protein
/ genetics
Epigenesis, Genetic
/ genetics
Germinal Center
/ physiology
HEK293 Cells
Humans
Lymphoma, Follicular
/ etiology
Lymphoma, Large B-Cell, Diffuse
/ genetics
Mice
Mice, Inbred C57BL
Sequence Deletion
/ genetics
Transcription, Genetic
/ genetics
CREBBP
EP300
acetyltransferase inhibitor
dark zone
diffuse large cell lymphoma
germinal center
light zone
synthetic lethality
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
17 09 2019
17 09 2019
Historique:
received:
06
02
2019
revised:
03
06
2019
accepted:
06
08
2019
pubmed:
15
9
2019
medline:
18
12
2019
entrez:
15
9
2019
Statut:
ppublish
Résumé
Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.
Identifiants
pubmed: 31519498
pii: S1074-7613(19)30332-2
doi: 10.1016/j.immuni.2019.08.006
pmc: PMC7362711
mid: NIHMS1539075
pii:
doi:
Substances chimiques
Acetyltransferases
EC 2.3.1.-
CREB-Binding Protein
EC 2.3.1.48
Crebbp protein, mouse
EC 2.3.1.48
E1A-Associated p300 Protein
EC 2.3.1.48
Ep300 protein, mouse
EC 2.3.1.48
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
535-547.e9Subventions
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA192937
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172492
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210105
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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