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Published on: June 6, 2025
Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in
Matilde Y Follo1, Carlo Finelli, Sara Mongiorgi
1Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Via Irnerio 48, Bologna, Italy.
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.
Insights
Phosphoinositide-phospholipase C beta 1 (PI-PLCbeta1) promoter hypermethylation is observed in high-risk myelodysplastic syndromes (MDS). PI-PLCbeta1 reactivation predicts response to azacitidine therapy in MDS patients.
Area of Science:
- Molecular biology
- Cancer research
- Hematology
Background:
- Lipid signaling pathways regulate cell functions and are implicated in myelodysplastic syndromes (MDS) progression to acute myeloid leukemia (AML).
- Mono-allelic deletion of phosphoinositide-phospholipase C beta 1 (PI-PLCbeta1) is linked to increased AML risk.
- PI-PLCbeta1 expression correlated with azacitidine response in a single MDS patient.
Purpose of the Study:
- To investigate the role of PI-PLCbeta1 promoter methylation in MDS.
- To determine if PI-PLCbeta1 gene reactivation predicts response to azacitidine therapy in MDS patients.
Main Methods:
- Analysis of PI-PLCbeta1 gene promoter structure.
- Quantification of PI-PLCbeta1 promoter methylation and gene expression in MDS patients at baseline and during azacitidine treatment.
Main Results:
- PI-PLCbeta1 promoter is hypermethylated in high-risk MDS patients.
- PI-PLCbeta1 mRNA levels increased, and promoter methylation decreased in patients responding to azacitidine.
- Molecular response correlated with and preceded clinical outcomes.
Conclusions:
- PI-PLCbeta1 promoter hypermethylation is a feature of high-risk MDS.
- PI-PLCbeta1 mRNA levels can predict clinical response to azacitidine.
- PI-PLCbeta1 reactivation represents a potential therapeutic strategy for MDS.