Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia.
BCL11B
CP: Cancer
CTCF mutation
T cell acute lymphoblastic leukemia
TLX3
competitive chromatin looping
enhancer insulation
oncogene regulation
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
25 04 2023
25 04 2023
Historique:
received:
25
10
2022
revised:
18
03
2023
accepted:
23
03
2023
medline:
4
10
2023
pubmed:
16
4
2023
entrez:
15
4
2023
Statut:
ppublish
Résumé
Monoallelic inactivation of CCCTC-binding factor (CTCF) in human cancer drives altered methylated genomic states, altered CTCF occupancy at promoter and enhancer regions, and deregulated global gene expression. In patients with T cell acute lymphoblastic leukemia (T-ALL), we find that acquired monoallelic CTCF-inactivating events drive subtle and local genomic effects in nearly half of t(5; 14) (q35; q32.2) rearranged patients, especially when CTCF-binding sites are preserved in between the BCL11B enhancer and the TLX3 oncogene. These solitary intervening sites insulate TLX3 from the enhancer by inducing competitive looping to multiple binding sites near the TLX3 promoter. Reduced CTCF levels or deletion of the intervening CTCF site abrogates enhancer insulation by weakening competitive looping while favoring TLX3 promoter to BCL11B enhancer looping, which elevates oncogene expression levels and leukemia burden.
Identifiants
pubmed: 37060567
pii: S2211-1247(23)00384-4
doi: 10.1016/j.celrep.2023.112373
pii:
doi:
Substances chimiques
BCL11B protein, human
0
CCCTC-Binding Factor
0
Chromatin
0
Repressor Proteins
0
Transcription Factors
0
Tumor Suppressor Proteins
0
CTCF protein, human
0
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
112373Subventions
Organisme : NCI NIH HHS
ID : R35 CA197695
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.