Journal
BLOOD CANCER DISCOVERY
Volume 1, Issue 3, Pages 274-289Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2643-3230.BCD-20-0059
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Funding
- European Research Council [StG-639784]
- Fund for Scientific Research Flanders
- Kom op tegen Kanker (Flemish Cancer Society)
- Stichting Tegen Kanker (STK)
- Kinderkankerfonds
- Cancer Research Institute Ghent (CRIG)
- National Science Center Poland [2017/24/T/NZ5/00359]
- National Centre for Research and Development Poland [STRATEGMED3/304586/5/NCBR/2017]
- Swedish Childhood Foundation [PR2018-0064]
- Medical Faculty of Umea University
- Kempe Foundation
- Lion's Cancer Research Foundation
- National Health and Medical Research Council of Australia [NHMRC APP1142627]
- National Cancer Institute [R01CA207530]
- Department of Veterans Affairs [I01BX001799]
- Indiana University School of Medicine Strategic Research Initiative
- Research Foundation -Flanders (FWO)
- Flemish Government-department EWI
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Cancer cells display DNA hypermethylation at specific 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 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.
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