Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS

Matilde Y. Follo, Carlo Finelli, Sara Mongiorgi, Cristina Clissa, Costanza Bosi, Nicoletta Testoni, Francesca Chiarini, Giulia Ramazzotti, Michele Baccarani, Alberto M. Martelli, Lucia Manzoli, Giovanni Martinelli, Lucio Cocco

Research output: Contribution to journalArticle

Abstract

Lipid signaling pathways are involved in cell growth, differentiation, and apoptosis, and could have a role in the progression of myelodysplastic syndromes (MDS) into acute myeloid leukemia (AML). Indeed, recent studies showed that phosphoinositide-phospholipase (PI-PL)Cbeta1 mono-allelic deletion correlates with a higher risk of AML evolution. Also, a single patient treated with azacitidine, a DNA methyltransferase inhibitor currently used in MDS, displayed a direct correlation between PI-PLCbeta1 gene expression and drug responsiveness. Consequently, we hypothesized that PI-PLCbeta1 could be a target for demethylating therapy. First, we analyzed the structure of PI-PLCbeta1 gene promoter, then quantified the degree of PI-PLCbeta1 promoter methylation and gene expression in MDS patients at baseline and during azacitidine administration. Indeed, PI-PLCbeta1 mRNA increased in responder patients, along with a reduction of PI-PLCbeta1 promoter methylation. Also, the molecular response correlated to and anticipated the clinical outcome, thus suggesting that PI-PLCbeta1 gene reactivation could predict azacitidine responsiveness. Our results demonstrate not only that PI-PLCbeta1 promoter is hypermethylated in high-risk MDS patients, but also that the amount of PI-PLCbeta1 mRNA could predict the clinical response to azacitidine, therefore indicating a promising new therapeutic approach.

Original languageEnglish
Pages (from-to)16811-16816
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number39
DOIs
Publication statusPublished - Sep 29 2009

Keywords

  • Epigenetic therapy
  • Inositides
  • Myelodysplastic syndromes
  • Real-time PCR
  • Signal transduction

ASJC Scopus subject areas

  • General

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  • Cite this

    Follo, M. Y., Finelli, C., Mongiorgi, S., Clissa, C., Bosi, C., Testoni, N., Chiarini, F., Ramazzotti, G., Baccarani, M., Martelli, A. M., Manzoli, L., Martinelli, G., & Cocco, L. (2009). Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS. Proceedings of the National Academy of Sciences of the United States of America, 106(39), 16811-16816. https://doi.org/10.1073/pnas.0907109106