O-027 European distribution of usage and impact on outcome for treatment with erythropoietic stimulating agents within the EUMDS lower-risk registry programme

an increased risk to develop acute myeloid leukemia (AML). While de novo MDS is predominantly found in elderly patients, childhood MDS is rather rare and often associated with genetic disorders and inherited bone marrow failure syndromes. Introduction: Recently, germline mutations in the hematopoietic transcription factor GATA2 were identified in familial cases of MDS. Epigenetic alterations represent a major pathogenetic mechanism in MDS and have been extensively researched in adults, while genomewide studies on deregulated epigenetic processes in childhood MDS are still lacking. Purpose: The goal of the presented study was to analyze aberrant DNAmethylation in familiar childhoodMDSby genome-widemethylation profiling. Materials and Methods: Therefore we obtained DNA methylation profiles across the genome in a cohort of childhood MDS samples as well as monocytes from healthy donors (control) using methylCpG-immunoprecipitation combined with next-generation sequencing. The MDS cohort consisted of 10 patients (5 female, 5 male; median age at diagnosis: 13.7 years; range 6.1-19) carrying different mutations in GATA2 (except for two siblings with an identitical mutation). Results: Our analysis showed that these 10 MDS patients exhibit methylation profiles distinct from healthy controls. Based on the degree of methylation, MDS patients could be clustered into subgroups with distinctive patterns. The subgroup with the highest degree of methylation was exclusively composed of patients with advanced morphological subtype (RAEB or RAEB-t) at diagnosis and aneuploidic karyotypes: monosomy 7 alone or monosomy 7 and trisomy 8. In contrast, most patients with DNA methylation patterns resembling normal control patterns were diagnosed with the less advanced refractory cytopenia subtype. Computational analyses of epigenetic and sequence features of aberrantly methylated regions demonstrated their frequent association with the PcG-mark H3K27me3 in hematopoietic stem cells as well as a distinct composition of transcription factor binding motifs. Conclusions: We present the first genome-wide analyses of aberrant DNA methylation in familiar childhood MDS sharing predisposing mutations in GATA2. Our data suggest that DNA methylation changes might be associated with morphologic subtype and disease progression and warrant further studies in larger cohorts.