Background: Azacitidine is a DNA methyltransferase inhibitor currently used for the treatment of higher-risk myelodysplastic syndromes (MDS) which has also been proven an effective treatment of lower-risk MDS (Silverman LR et al, J Clin Oncol 2002; Musto P et al, Cancer 2010). Inositide signalling is involved in cell growth, differentiation and apoptosis, therefore affecting cell processes and playing a role in the pathogenesis of several malignancies. Introduction: Our group recently demonstrated that phosphoinositide-phospholipase C beta1 (PI-PLCbeta1) is involved in the MDS progression to AML and is affected by epigenetic therapy (Follo MY et al, J Cell Biochem 2010; Follo MY et al, Leukemia 2010). Namely, PI-PLCbeta1 specifically targets Cyclin D3, which is in turn implicated in hematopoietic stem cell proliferation and differentiation. Purpose: In this study, we analyzed the role of PI-PLCbeta1- dependent signalling pathways during epigenetic therapy, focusing on the effect of azacitidine on PI-PLCbeta1 downstream target Cyclin D3 in lower-risk MDS patients. Materials and Methods: The analysis included 25 patients (IPSS risk: low or intermediate-1) treated with azacitidine alone (75 mg/m2 subcutaneous daily for 5 consecutive days every 28 days, for a total of 8 courses). For each patient we followed the effect of azacitidine in correlation to both PI-PLCbeta1 and Cyclin D3 expression. Results: Our results show that 9/25 (36%) of our lower-risk MDS patients showed a hematologic response to azacitidine (Complete Remission: 4 patients, Partial Remission: 1 patient, Hematologic Improvements: 4 patients), as well as an increase in PI-PLCbeta1 expression, as compared with pre-treatment levels. Furthermore, ongoing analyses are trying to disclose whether Cyclin D3 activation is also implicated in azacitidine response, therefore affecting hematopoietic stem cell differentiation processes. Conclusions: Overall, our data hint at a correlation between azacitidine therapy and PI-PLCbeta1 signalling, possibly via the activation of Cyclin D3, even in lower-risk MDS, thus indicating that PI-PLCbeta1 could be useful not only for evaluating the efficacy of azacitidine but also for disclosing the molecular mechanisms underlying this kind of treatment in lower-risk MDS
M.Y. Follo, S. Mongiorgi, C. Clissa, C. Filì, C. Colombi, M. Baccarani, et al. (2011). Effect of azacitidine on inositide-dependent signalling pathways in low-risk MDS patients [10.1016/S0145-2126(11)70242-9].
Effect of azacitidine on inositide-dependent signalling pathways in low-risk MDS patients
FOLLO, MATILDE YUNG;MONGIORGI, SARA;BACCARANI, MICHELE;MARTINELLI, GIOVANNI;MANZOLI, LUCIA;FINELLI, CARLO;COCCO, LUCIO ILDEBRANDO
2011
Abstract
Background: Azacitidine is a DNA methyltransferase inhibitor currently used for the treatment of higher-risk myelodysplastic syndromes (MDS) which has also been proven an effective treatment of lower-risk MDS (Silverman LR et al, J Clin Oncol 2002; Musto P et al, Cancer 2010). Inositide signalling is involved in cell growth, differentiation and apoptosis, therefore affecting cell processes and playing a role in the pathogenesis of several malignancies. Introduction: Our group recently demonstrated that phosphoinositide-phospholipase C beta1 (PI-PLCbeta1) is involved in the MDS progression to AML and is affected by epigenetic therapy (Follo MY et al, J Cell Biochem 2010; Follo MY et al, Leukemia 2010). Namely, PI-PLCbeta1 specifically targets Cyclin D3, which is in turn implicated in hematopoietic stem cell proliferation and differentiation. Purpose: In this study, we analyzed the role of PI-PLCbeta1- dependent signalling pathways during epigenetic therapy, focusing on the effect of azacitidine on PI-PLCbeta1 downstream target Cyclin D3 in lower-risk MDS patients. Materials and Methods: The analysis included 25 patients (IPSS risk: low or intermediate-1) treated with azacitidine alone (75 mg/m2 subcutaneous daily for 5 consecutive days every 28 days, for a total of 8 courses). For each patient we followed the effect of azacitidine in correlation to both PI-PLCbeta1 and Cyclin D3 expression. Results: Our results show that 9/25 (36%) of our lower-risk MDS patients showed a hematologic response to azacitidine (Complete Remission: 4 patients, Partial Remission: 1 patient, Hematologic Improvements: 4 patients), as well as an increase in PI-PLCbeta1 expression, as compared with pre-treatment levels. Furthermore, ongoing analyses are trying to disclose whether Cyclin D3 activation is also implicated in azacitidine response, therefore affecting hematopoietic stem cell differentiation processes. Conclusions: Overall, our data hint at a correlation between azacitidine therapy and PI-PLCbeta1 signalling, possibly via the activation of Cyclin D3, even in lower-risk MDS, thus indicating that PI-PLCbeta1 could be useful not only for evaluating the efficacy of azacitidine but also for disclosing the molecular mechanisms underlying this kind of treatment in lower-risk MDSI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
