Nuclear lipid metabolism has widely been implicated in cell growth, differentiation and neoplastic transformation. Phosphoinositide- phospholipase C (PI-PLC) b-1 is a key enzyme in nuclear signal transduction, and it is involved in many cellular processes, such as proliferation and differentiation.1 The involvement of PI-PLCb-1 in hematopoietic differentiation prompted us to investigate the role of this signaling molecule in hematological malignancies, focusing particularly on patients affected by myelodysplastic syndromes (MDS) at higher risk of evolution into acute myeloid leukemia (AML). By using fluorescence in situ hybridization (FISH) analysis, our group demonstrated, in a small number of high-risk MDS patients,2 that subjects bearing a mono-allelic cryptic deletion of the PIPLCb- 1 gene had a worse clinical outcome, as compared with patients having both alleles. In a subsequent study, it has also been shown that the expression profile of both PI-PLCb-1a and PI-PLCb-1b mRNAs, which are the two alternative splicing isoforms of PI-PLCb-1, is altered in high-risk MDS, as compared to healthy donors.3 Interestingly, MDS cells always expressed higher levels of PI-PLCb-1b mRNA as compared to PI-PLCb-1a mRNA; this difference may reflect a specific role of PI-PLCb-1 in MDS, given that the PI-PLCb-1a splicing isoform demonstrates both nuclear and cytoplasmatic localization, while PI-PLCb-1b splicing isoform is localized only in the nucleus. Furthermore, our recent studies demonstrated that not only is Akt specifically phosphorylated in high-risk MDS patients, but also mTOR and its downstream targets are activated,4 affecting cell survival and proliferation of MDS cells.
PI-PLCbeta-1 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes.
Martelli AM;
2008
Abstract
Nuclear lipid metabolism has widely been implicated in cell growth, differentiation and neoplastic transformation. Phosphoinositide- phospholipase C (PI-PLC) b-1 is a key enzyme in nuclear signal transduction, and it is involved in many cellular processes, such as proliferation and differentiation.1 The involvement of PI-PLCb-1 in hematopoietic differentiation prompted us to investigate the role of this signaling molecule in hematological malignancies, focusing particularly on patients affected by myelodysplastic syndromes (MDS) at higher risk of evolution into acute myeloid leukemia (AML). By using fluorescence in situ hybridization (FISH) analysis, our group demonstrated, in a small number of high-risk MDS patients,2 that subjects bearing a mono-allelic cryptic deletion of the PIPLCb- 1 gene had a worse clinical outcome, as compared with patients having both alleles. In a subsequent study, it has also been shown that the expression profile of both PI-PLCb-1a and PI-PLCb-1b mRNAs, which are the two alternative splicing isoforms of PI-PLCb-1, is altered in high-risk MDS, as compared to healthy donors.3 Interestingly, MDS cells always expressed higher levels of PI-PLCb-1b mRNA as compared to PI-PLCb-1a mRNA; this difference may reflect a specific role of PI-PLCb-1 in MDS, given that the PI-PLCb-1a splicing isoform demonstrates both nuclear and cytoplasmatic localization, while PI-PLCb-1b splicing isoform is localized only in the nucleus. Furthermore, our recent studies demonstrated that not only is Akt specifically phosphorylated in high-risk MDS patients, but also mTOR and its downstream targets are activated,4 affecting cell survival and proliferation of MDS cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
