DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.
Journal
Genome research
ISSN: 1549-5469
Titre abrégé: Genome Res
Pays: United States
ID NLM: 9518021
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
23
07
2020
accepted:
09
03
2021
pubmed:
13
3
2021
medline:
11
3
2022
entrez:
12
3
2021
Statut:
ppublish
Résumé
Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved subclassification and understanding of the biology of the disease. Here, we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed "epitypes") using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes showed developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem-cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer, and repressed regions. Patients in epitypes with stem-cell-like methylation features showed inferior overall survival along with up-regulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated with
Identifiants
pubmed: 33707228
pii: gr.269233.120
doi: 10.1101/gr.269233.120
pmc: PMC8092005
doi:
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
747-761Subventions
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217862
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224019
Pays : United States
Informations de copyright
© 2021 Giacopelli et al.; Published by Cold Spring Harbor Laboratory Press.
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