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Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS. (Articolo in rivista)

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Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS. (Articolo in rivista) (literal)

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Follo MY, Finelli C, Mongiorgi S, Clissa C, Bosi C, Testoni N, Chiarini F, Ramazzotti G, Baccarani M, Martelli AM, Manzoli L, Martinelli G, Cocco L. (2009)
Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS.
in Proceedings of the National Academy of Sciences of the United States of America
(literal)

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Follo MY, Finelli C, Mongiorgi S, Clissa C, Bosi C, Testoni N, Chiarini F, Ramazzotti G, Baccarani M, Martelli AM, Manzoli L, Martinelli G, Cocco L. (literal)

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Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; Institute of Hematology and Medical Oncology L. e A. Sera` gnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; Hematology Unit, Ospedale Civile di Piacenza, Via Taverna 49, 29100 Piacenza, Italy; Istituto per i Trapianti dOrgano e lImmunocitologia, Consiglio Nazionale delle Ricerche, Sezione di Bologna c/o I.O.R., Via di Barbiano 1/10, 40136 Bologna, Italy (literal)

Titolo

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

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. (literal)

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