Aging of Preleukemic Thymocytes Drives CpG Island Hypermethylation in T-cell Acute Lymphoblastic Leukemia
Juliette Roels, Morgan Thénoz, Bronisława Szarzyńska‐Zawadzka, 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 Nieuwerburgh, Laurence C. Cheung, Rishi S. Kotecha, Marc R. Mansour, Bart Ghesquière, Guy Van Camp, Wim Vanden Berghe, Jerzy Kowalczyk, Tomasz Szczepański, Utpal P. Davé, Andreas E. Kulozik, Steven Goossens, David J. Curtis, Tom Taghon, Małgorzata Dawidowska, Sofie Degerman, Pieter Van Vlierberghe
Abstract
Abstract Cancer cells display DNA hypermethylation at specific CpG islands in comparison with 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 that display a reciprocal association with H3K27me3 binding. In addition, we reveal that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in preleukemic, 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 provide conceptual evidence for the involvement of a preleukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL. Significance: We developed a DNA methylation signature that reveals the epigenetic history of thymocytes during T-cell transformation. This human signature was recapitulated by murine self-renewing preleukemic thymocytes that build an age-related CpG island hypermethylation phenotype, providing conceptual evidence for the involvement of a preleukemic thymic phase in human T-cell leukemia. This article is highlighted in the In This Issue feature, p. 215