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

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Authors
Roels, Juliette
Thénoz, Morgan
Szarzyńska, Bronisława
Landfors, Mattias
De Coninck, Stien
Demoen, Lisa
Provez, Lien
Kuchmiy, Anna
Strubbe, Steven
Reunes, Lindy
Pieters, Tim
Matthijssens, Filip
Van Loocke, Wouter
Erarslan-Uysal, Büşra
Richter-Pechańska, Paulina
Declerck, Ken
Lammens, Tim
De Moerloose, Barbara
Deforce, Dieter
Van Nieuwerburgh, Filip
Cheung, Laurence
Kotecha, Rishi S
Mansour, Marc R
Ghesquière, Bart
Van Camp, Guy
Berghe, Wim Vanden
Kowalczyk, Jerzy R
Szczepański, Tomasz
Davé, Utpal P
Kulozik, Andreas E
Goossens, Steven
Curtis, David J
Taghon, Tom
Dawidowska, Małgorzata
Degerman, Sofie
Van Vlierberghe, Pieter
Date
2020
Type
Journal Article

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Citation
Roels, J. and Thénoz, M. and Szarzyńska, B. and Landfors, M. and De Coninck, S. and Demoen, L. and Provez, L. et al. 2020. Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia. Blood Cancer Discovery. 1 (3): pp. 274-289.
Source Title
Blood Cancer Discovery
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Faculty
Faculty of Health Sciences
School
School of Pharmacy and Biomedical Sciences
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Abstract

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.