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Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2020 (English)In: Blood cancer discovery, ISSN 2643-3249, Vol. 1, no 3, p. 274-289Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2020. Vol. 1, no 3, p. 274-289
Keywords [en]
DNA methylation, Decitabine, T-ALL, aging, self-renewing thymocytes
National Category
Cancer and Oncology Hematology
Identifiers
URN: urn:nbn:se:umu:diva-176999DOI: 10.1158/2643-3230.BCD-20-0059ISI: 000713094100007PubMedID: 33179015Scopus ID: 2-s2.0-85100020409OAI: oai:DiVA.org:umu-176999DiVA, id: diva2:1503359
Funder
The Kempe FoundationsAvailable from: 2020-11-24 Created: 2020-11-24 Last updated: 2023-09-19Bibliographically approved

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Landfors, MattiasDegerman, Sofie

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CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
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