title: Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS.
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.
authors.affiliation: Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: Matilde Y
authors.initials: MY
authors.lastname: Follo
authors.forename: Carlo
authors.initials: C
authors.lastname: Finelli
authors.forename: Sara
authors.initials: S
authors.lastname: Mongiorgi
authors.forename: Cristina
authors.initials: C
authors.lastname: Clissa
authors.forename: Costanza
authors.initials: C
authors.lastname: Bosi
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Testoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
authors.forename: Giulia
authors.initials: G
authors.lastname: Ramazzotti
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Manzoli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000201:enzymology*; D054801:Phosphoinositide Phospholipase C / Q000235:genetics / Q000378:metabolism*; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D054801:Phosphoinositide Phospholipase C; D054799:Phospholipase C beta; D001374:Azacitidine