Phosphoinositide-specific phospholipase C (PI-PLC) beta1 is a key enzyme in nuclear signal transduction, and it is involved in many cellular processes, such as proliferation and differentiation (Manzoli L et al, Prog Lipid Res, 2005). In particular, the involvement of the PI-PLCbeta1 gene in erythroid differentiation lead us to investigate this gene in patients affected by high-risk Myelodysplastic Syndromes (MDS). It is still unclear what is the pathogenesis of the evolution of MDS into Acute Myeloid Leukemia (AML), even if the presence of a mono-allelic and cryptic deletion of the PI-PLCbeta1 gene, as well as an impaired regulation of the PI3K/Akt/mTOR axis, have been recently hypothesized to be implicated in mechanisms related to the disease progression (Lo Vasco VR et al, Leukemia, 2004; Follo MY et al, Cancer Res, 2007). In the present study, we performed a relative quantification, by Real-Time Polymerase Chain Reaction (PCR) analysis, on high-risk MDS patients, at baseline and during treatment with azacitidine. Furthermore, we evaluated the expression of the PI-PLCbeta1 gene on healthy donors and the HL60 cell line, which is useful for testing the accuracy of the technology because of its low expression of PI-PLCbeta1. To analyze and quantify the levels of the two different splicing variants of the PI-PLCbeta1 gene (a and b), we used a TaqMan isoform specific approach. We studied 8 patients with high-risk MDS (IPSS risk high or intermediate-II) treated with azaciditine, 5 of them showing a favourable response to treatment (1 patient: complete remission; 2 patients: partial remission; 2 patients: haematologic improvement). During the treatment with azacitidine, the non responsive patients (3/8) did not show any significant change in the levels of PI-PLCbeta1 mRNAs, whilst all the responders showed a marked increase of the PI-PLCbeta1 mRNA as compared with their baseline amount. Interestingly, the responsive patients showed fluctuations of PI-PLCbeta1 levels that could be related to their clinical status.Our data show a correlation between azacitidine treatment and PI-PLCbeta1 signalling in high-risk MDS, hinting at the likelihood that azacitidine could affect the transcriptional activity of PI-PLCbeta1, which is indeed a key player in the control of cell cycle.
PI-PLCbeta1 Expression in Patients with High-Risk Myelodysplastic Syndromes Is Affected by Azacitidine Treatment.
FINELLI, CARLO;FOLLO, MATILDE YUNG;MONGIORGI, SARA;CLISSA, CRISTINA;MARTINELLI, GIOVANNI;BACCARANI, MICHELE;MARTELLI, ALBERTO MARIA;COCCO, LUCIO ILDEBRANDO
2007
Abstract
Phosphoinositide-specific phospholipase C (PI-PLC) beta1 is a key enzyme in nuclear signal transduction, and it is involved in many cellular processes, such as proliferation and differentiation (Manzoli L et al, Prog Lipid Res, 2005). In particular, the involvement of the PI-PLCbeta1 gene in erythroid differentiation lead us to investigate this gene in patients affected by high-risk Myelodysplastic Syndromes (MDS). It is still unclear what is the pathogenesis of the evolution of MDS into Acute Myeloid Leukemia (AML), even if the presence of a mono-allelic and cryptic deletion of the PI-PLCbeta1 gene, as well as an impaired regulation of the PI3K/Akt/mTOR axis, have been recently hypothesized to be implicated in mechanisms related to the disease progression (Lo Vasco VR et al, Leukemia, 2004; Follo MY et al, Cancer Res, 2007). In the present study, we performed a relative quantification, by Real-Time Polymerase Chain Reaction (PCR) analysis, on high-risk MDS patients, at baseline and during treatment with azacitidine. Furthermore, we evaluated the expression of the PI-PLCbeta1 gene on healthy donors and the HL60 cell line, which is useful for testing the accuracy of the technology because of its low expression of PI-PLCbeta1. To analyze and quantify the levels of the two different splicing variants of the PI-PLCbeta1 gene (a and b), we used a TaqMan isoform specific approach. We studied 8 patients with high-risk MDS (IPSS risk high or intermediate-II) treated with azaciditine, 5 of them showing a favourable response to treatment (1 patient: complete remission; 2 patients: partial remission; 2 patients: haematologic improvement). During the treatment with azacitidine, the non responsive patients (3/8) did not show any significant change in the levels of PI-PLCbeta1 mRNAs, whilst all the responders showed a marked increase of the PI-PLCbeta1 mRNA as compared with their baseline amount. Interestingly, the responsive patients showed fluctuations of PI-PLCbeta1 levels that could be related to their clinical status.Our data show a correlation between azacitidine treatment and PI-PLCbeta1 signalling in high-risk MDS, hinting at the likelihood that azacitidine could affect the transcriptional activity of PI-PLCbeta1, which is indeed a key player in the control of cell cycle.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
