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

Tijdschriftbijdrage - Tijdschriftartikel

Cancer cells display DNA hypermethylation at specifi c CpG islands in comparison with their normal healthy counterparts, but the mechanism that drives this socalled 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 profi le refl ects 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.
Volume: 1
Pagina's: 274 - 289
Jaar van publicatie:2020