Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia.
DNA methylation
Decitabine
T-ALL
aging
self-renewing thymocytes
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
entrez:
12
11
2020
pubmed:
13
11
2020
medline:
13
11
2020
Statut:
ppublish
Résumé
Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in pre-leukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.
Identifiants
pubmed: 33179015
doi: 10.1158/2643-3230.BCD-20-0059
pmc: PMC7116343
mid: EMS102743
pii: 2643-3230.BCD-20-0059
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Pagination
274-289Subventions
Organisme : Blood Cancer UK
ID : 17002
Pays : United Kingdom
Organisme : European Research Council
ID : 639784
Pays : International
Organisme : BLRD VA
ID : I01 BX001799
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207530
Pays : United States
Déclaration de conflit d'intérêts
Conflicts of Interest The authors declare no potential conflicts of interest.
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