Epigenetic signature of ionizing radiation in therapy-related AML patients

Therapy-related acute myeloid leukaemia (t-AML) is a late adverse effect of previous chemotherapy(ct-AML) and/or radiotherapy (rt-AML) or immunosuppressive treatment. t-AMLs represent ~10-20% of all AML cases, are extremely aggressive and have a poor prognosis in comparison to de novo AML. We hypothesised that in rt-AML, exposure to radiation leads to genome-wide epigenetic modifications. An epigenome-wide association study was conducted, measuring over 850K methylation sites across the whole genome in 14 donors. We focused on 94K sites lying in CpG-rich gene promoter regions. Overall, we found genome-wide hypo-methylation in AML and identified specific genes with promoter hyper-methylation. Additionally, pyrosequencing was used to quantify the methylation in 24 samples. We confirmed that the promoters of the genes MEST and GATA5, both previously reported as tumour suppressors, were specifically hyper-methylated in rt-AML in comparison to control and other subtypes of t-AML. These may represent the epigenetic contribution to rt-AML development at the molecular level and be potential drug targets in rt-AML. Illumina Infinium Human Methylation 450 K array for 12 patients: 5 de novo AMLs, 4 ct-AMLs and 3 rt-AMLs and Illumina Infinium Human Methylation EPIC Array in two batches: 3 de novo AML patients, 3 ct-AML patients and 2 rt-AML patients in the first batch, and 5 healthy donors, 2 de novo AML patients and 1 combined radio- and chemotherapy patient in the second batch.