title: Epigenetic changes in therapy-related MDS/AML.
abstract: Therapy-related Myelodysplastic Syndromes/Acute Myeloid Leukemias (t-MDS/AML) are one of the most compelling long term adverse events occurring in cancer survivors treated with chemo-radiotherapy regimes. Beside several well-described genetic lesions, a growing amount of data suggests that abnormalities in DNA methylation profile contribute to multistep secondary leukemogenesis. Two distinct alterations of normal DNA methylation patterns may occur in cancer: a global hypomethylation resulting in chromosomal instability and loss of genetic integrity, and promoter specific DNA hypermethylation which leads to silencing of tumor suppressor genes. Cytotoxic drugs and radiation have been shown to affect tissue DNA methylation profile. Radiation is able to induce a stable DNA hypomethylation in both target and bystander tissues. Gene promoter methylation is a common finding in t-MDS/AML and has been associated to a shorter latency period from the treatment of the primary tumor. Among the studied genes, p15 methylation correlated to monosomy/deletion of chromosome 7q, suggesting that it could be a relevant event in alkylating agent-induced leukemogenesis. We found frequent methylation of DAPK in the t-MDS/AML group, especially in patients with a previous lymphoproliferative disease. In patients studied for concurrent methylation of several promoters, t-MDS/AML were significantly more frequently hypermethylated in 2 or more promoter regions than de novo MDS or AML suggesting that promoter hypermethylation of genes involved in cell cycle control, apoptosis and DNA repair pathways is a frequent finding in t-MDS/AML and may contribute to secondary leukemogenesis. However, how the epigenetic machinery is disrupted after chemo/radiotherapy and during secondary carcinogenesis is still unknown, warranting further studies.
authors.affiliation: Istituto di Ematologia, Università Cattolica Sacro Cuore, Largo A Gemelli 8, 00168Rome, Italy. mtvoso@rm.unicatt.it
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Voso
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Alò
authors.forename: Mariangela
authors.initials: M
authors.lastname: Greco
authors.forename: Emiliano
authors.initials: E
authors.lastname: Fabiani
authors.forename: Marianna
authors.initials: M
authors.lastname: Criscuolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Migliara
authors.forename: Livio
authors.initials: L
authors.lastname: Pagano
authors.forename: Luana
authors.initials: L
authors.lastname: Fianchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Guidi
authors.forename: Stefan
authors.initials: S
authors.lastname: Hohaus
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leone
mesh_terms: D004249:DNA Damage; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000628:therapy; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000628:therapy