Epigenomic profiling of glucocorticoid responses identifies cis-regulatory disruptions impacting steroid resistance in childhood acute lymphoblastic leukemia.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
02
05
2022
accepted:
11
08
2022
revised:
10
08
2022
pubmed:
27
8
2022
medline:
4
10
2022
entrez:
26
8
2022
Statut:
ppublish
Résumé
Glucocorticoids (GCs) are a mainstay of contemporary, multidrug chemotherapy in the treatment of childhood acute lymphoblastic leukemia (ALL), and resistance to GCs remains a major clinical concern. Resistance to GCs is predictive of ALL relapse and poor clinical outcome, and therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes implicated in GC resistance, there remains an insufficient understanding of the impact of cis-regulatory disruptions in resistance. To address this, we mapped the gene regulatory response to GCs in two ALL cell lines using functional genomics and high-throughput reporter assays and identified thousands of GC-responsive changes to chromatin state, including the formation of over 250 GC-responsive super-enhancers and a depletion of AP-1 bound cis-regulatory elements implicated in cell proliferation and anti-apoptotic processes. By integrating our GC response maps with genetic and epigenetic datasets in primary ALL cells from patients, we further uncovered cis-regulatory disruptions at GC-responsive genes that impact GC resistance in childhood ALL. Overall, these data indicate that GCs initiate pervasive effects on the leukemia epigenome, and that alterations to the GC gene regulatory network contribute to GC resistance.
Identifiants
pubmed: 36028659
doi: 10.1038/s41375-022-01685-z
pii: 10.1038/s41375-022-01685-z
pmc: PMC9522591
mid: NIHMS1833642
doi:
Substances chimiques
Chromatin
0
Glucocorticoids
0
Receptors, Glucocorticoid
0
Steroids
0
Transcription Factor AP-1
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
2374-2383Subventions
Organisme : NCI NIH HHS
ID : R01 CA234490
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM115279
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Informations de copyright
© 2022. The Author(s).
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