RNA-sequencing of T-cell Acute Lymphoblastic Leukemia (T-ALL) and human CD34+ thymocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE200857 | GEO | 2023/05/10
REPOSITORIES: GEO
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Project description: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 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 found that this aberrant methylation profile shows a strong correlation with the epigenetic age of the leukemic T cells and elucidate that a similar CpG island methylation signature is gradually established in aging pre-leukemic thymocytes from CD2-Lmo2 transgenic mice. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, our work demonstrates that DNA methylation reflects the epigenetic history of leukemic T cells and suggests that methylation-based subtypes of human T-ALL have followed a different trajectory towards T-cell transformation, possibly mediated by differences in the self-renewing capacity of the putative T-ALL cell-of-origin. Given that the concept of preleukemic thymocytes has only been reported in T-ALL mouse models so far, we here provide, for the first time, conceptual evidence that a pre-leukemic phase might also be involved in the pathogenesis of the human disease.
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| S-EPMC4319237 | biostudies-literature