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Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia

Roels, Juliette (author)
Thénoz, Morgan (author)
Szarzyńska, Bronisława (author)
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Landfors, Mattias, 1977- (author)
Umeå universitet,Patologi
De Coninck, Stien (author)
Demoen, Lisa (author)
Provez, Lien (author)
Kuchmiy, Anna (author)
Strubbe, Steven (author)
Reunes, Lindy (author)
Pieters, Tim (author)
Matthijssens, Filip (author)
Van Loocke, Wouter (author)
Erarslan-Uysal, Büşra (author)
Richter-Pechańska, Paulina (author)
Declerck, Ken (author)
Lammens, Tim (author)
De Moerloose, Barbara (author)
Deforce, Dieter (author)
Van Nieuwerburgh, Filip (author)
Cheung, Laurence C. (author)
Kotecha, Rishi S. (author)
Mansour, Marc R. (author)
Ghesquière, Bart (author)
Van Camp, Guy (author)
Berghe, Wim Vanden (author)
Kowalczyk, Jerzy R. (author)
Szczepański, Tomasz (author)
Davé, Utpal P. (author)
Kulozik, Andreas E. (author)
Goossens, Steven (author)
Curtis, David J. (author)
Taghon, Tom (author)
Dawidowska, Małgorzata (author)
Degerman, Sofie, 1977- (author)
Umeå universitet,Institutionen för klinisk mikrobiologi,Patologi,Sofie Degerman
Van Vlierberghe, Pieter (author)
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 (creator_code:org_t)
American Association for Cancer Research, 2020
2020
English.
In: Blood cancer discovery. - : American Association for Cancer Research. - 2643-3249. ; 1:3, s. 274-289
Related links:
https://urn.kb.se/re...
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

Keyword

DNA methylation
Decitabine
T-ALL
aging
self-renewing thymocytes

Publication and Content Type

ref (subject category)
art (subject category)

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