Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment

M. Y. Follo, D. Russo, C. Finelli, S. Mongiorgi, C. Clissa, C. Fil, C. Colombi, M. Gobbi, L. Manzoli, M. Piazzi, A. M. Martelli, L. Cocco

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation.

Original languageEnglish
Pages (from-to)943-950
Number of pages8
JournalLeukemia
Volume26
Issue number5
DOIs
Publication statusPublished - May 2012

Keywords

  • azacitidine
  • methylation
  • myelodysplastic syndromes
  • nuclear signaling
  • PI-PLCbeta1

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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