A distinct epigenetic program underlies the 1;7 translocation in myelodysplastic syndromes

• Published in: Leukemia Vol. 33; no. 10; pp. 2481 - 2494
• Main Authors: Fernandez, Anair Graciela Lema, Crescenzi, Barbara, Pierini, Valentina, Di Battista, Valeria, Barba, Gianluca, Pellanera, Fabrizia, Di Giacomo, Danika, Roti, Giovanni, Piazza, Rocco, Adelman, Emmalee R., Figueroa, Maria E., Mecucci, Cristina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2019; Nature Publishing Group
• Subjects: 38/23; 38/32; 38/91; 45/29; 45/61; 631/208/68/2486; 631/67/1990/1673; Adult; Aged; Aged, 80 and over; Binding sites; Binding Sites - genetics; Cancer Research; Care and treatment; Chemotherapy; Chromosome 1; Chromosome Disorders - genetics; Critical Care Medicine; Cytogenetics; Deregulation; Disorders; Down-Regulation - genetics; Enhancers; Epigenesis, Genetic - genetics; Epigenetic inheritance; Epigenetics; Epigenomics - methods; Female; Gene expression; Genes; Genetic analysis; Genetic aspects; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Karyotyping - methods; Lipids; Male; Medicine; Medicine & Public Health; Middle Aged; Monosomy; Monosomy - genetics; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Neoplasms; Oncology; p53 Protein; Radiation therapy; Retrospective Studies; Ribonucleic acid; RNA; Transcription, Genetic - genetics; Translocation; Translocation (Genetics); Translocation, Genetic - genetics; Trisomy; Trisomy - genetics; Italy
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0433-9

The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Krüppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.