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

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

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19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)274-289
Number of pages16
JournalBlood Cancer Discovery
Volume1
Issue number3
DOIs
Publication statusPublished - Nov 2020

Keywords

  • aging
  • Decitabine
  • DNA methylation
  • self-renewing thymocytes
  • T-ALL

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