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

Anair Graciela Lema Fernandez, Barbara Crescenzi, Valentina Pierini, Valeria Di Battista, Gianluca Barba, Fabrizia Pellanera, Danika Di Giacomo, Giovanni Roti, Rocco Piazza, Emmalee R. Adelman, Maria Figueroa, Cristina Mecucci

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalLeukemia
DOIs
StatePublished - Jan 1 2019

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Myelodysplastic Syndromes
Epigenomics
Down-Regulation
Genes
Monosomy
Gene Ontology
ATP-Binding Cassette Transporters
Second Primary Neoplasms
Trisomy
p53 Genes
Radio
Cytogenetics
Transcription Factors
Up-Regulation
Binding Sites
RNA
Lipids
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Fernandez, A. G. L., Crescenzi, B., Pierini, V., Di Battista, V., Barba, G., Pellanera, F., ... Mecucci, C. (2019). A distinct epigenetic program underlies the 1;7 translocation in myelodysplastic syndromes. Leukemia. https://doi.org/10.1038/s41375-019-0433-9

A distinct epigenetic program underlies the 1;7 translocation in myelodysplastic syndromes. / 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; Mecucci, Cristina.

In: Leukemia, 01.01.2019.

Research output: Contribution to journalArticle

Fernandez, AGL, Crescenzi, B, Pierini, V, Di Battista, V, Barba, G, Pellanera, F, Di Giacomo, D, Roti, G, Piazza, R, Adelman, ER, Figueroa, M & Mecucci, C 2019, 'A distinct epigenetic program underlies the 1;7 translocation in myelodysplastic syndromes', Leukemia. https://doi.org/10.1038/s41375-019-0433-9
Fernandez AGL, Crescenzi B, Pierini V, Di Battista V, Barba G, Pellanera F et al. A distinct epigenetic program underlies the 1;7 translocation in myelodysplastic syndromes. Leukemia. 2019 Jan 1. https://doi.org/10.1038/s41375-019-0433-9
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 ; Mecucci, Cristina. / A distinct epigenetic program underlies the 1;7 translocation in myelodysplastic syndromes. In: Leukemia. 2019.
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abstract = "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 Kr{\"u}ppel-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.",
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AU - Barba, Gianluca

AU - Pellanera, Fabrizia

AU - Di Giacomo, Danika

AU - Roti, Giovanni

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