Profiling chromatin accessibility in pediatric acute lymphoblastic leukemia identifies subtype-specific chromatin landscapes and gene regulatory networks.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
09
09
2020
accepted:
24
02
2021
revised:
03
02
2021
pubmed:
15
3
2021
medline:
31
12
2021
entrez:
14
3
2021
Statut:
ppublish
Résumé
Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy comprised of molecular subtypes largely characterized by aneuploidy or recurring chromosomal rearrangements. Despite extensive information on the ALL transcriptome and methylome, there is limited understanding of the ALL chromatin landscape. We therefore mapped accessible chromatin in 24 primary ALL cell biospecimens comprising three common molecular subtypes (DUX4/ERG, ETV6-RUNX1 and hyperdiploid) from patients treated at St. Jude Children's Research Hospital. Our findings highlight extensive chromatin reprogramming in ALL, including the identification ALL subtype-specific chromatin landscapes that are additionally modulated by genetic variation. Chromatin accessibility differences between ALL and normal B-cells implicate the activation of B-cell repressed chromatin domains and detail the disruption of normal B-cell development in ALL. Among ALL subtypes, we uncovered roles for basic helix-loop-helix, homeodomain and activator protein 1 transcription factors in promoting subtype-specific chromatin accessibility and distinct gene regulatory networks. In addition to chromatin subtype-specificity, we further identified over 3500 DNA sequence variants that alter the ALL chromatin landscape and contribute to inter-individual variability in chromatin accessibility. Collectively, our data suggest that subtype-specific chromatin landscapes and gene regulatory networks impact ALL biology and contribute to transcriptomic differences among ALL subtypes.
Identifiants
pubmed: 33714976
doi: 10.1038/s41375-021-01209-1
pii: 10.1038/s41375-021-01209-1
pmc: PMC8435544
mid: NIHMS1713775
doi:
Substances chimiques
Chromatin
0
Transcription Factors
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
3078-3091Subventions
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM115279
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA036401
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234490
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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