title: Activation of nuclear inositide signalling pathways during erythropoietin therapy in low-risk MDS patients.
abstract: Inositide signaling pathways can have a role in the Myelodysplastic Syndromes (MDS) progression to acute myeloid leukemia. Erythropoietin (EPO) is currently used in low-risk MDS, where it successfully corrects anemia in 50-70% of patients. However, some MDS patients are refractory to this treatment and little is known about the exact molecular mechanisms underlying the effect of EPO in these subjects. Here, we investigated the role of inositide pathways in low-risk MDS treated with EPO, mainly focusing on the Akt/PI-PLC (Phosphoinositide-Phospholipase C) gamma1 axis, which is activated by the EPO receptor, and PI-PLCbeta1/Cyclin D3 signaling, as Cyclin D3 is associated with hematopoietic proliferation and differentiation. Interestingly, EPO responder patients showed a specific activation of both the Akt/PI-PLCgamma1 pathway and beta-Globin gene expression, while nonresponders displayed an increase in PI-PLCbeta1 signaling. Moreover, in normal CD34+ cells induced to erythroid differentiation, PI-PLCbeta1 overexpression abrogated both EPO-induced Akt phosphorylation and beta-Globin expression. Overall, these findings suggest that PI-PLCbeta1 can act as a negative regulator of erythroid differentiation and confirm the involvement of Akt/PI-PLCgamma1 pathway in EPO signaling, therefore contributing to the comprehension of the effect of EPO in low-risk MDS and possibly paving the way to the identification of MDS patients at higher risk of refractoriness to EPO treatment.
authors.affiliation: Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Bologna, Italy.
authors.forename: M Y
authors.initials: MY
authors.lastname: Follo
authors.forename: S
authors.initials: S
authors.lastname: Mongiorgi
authors.forename: C
authors.initials: C
authors.lastname: Clissa
authors.forename: S
authors.initials: S
authors.lastname: Paolini
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
authors.forename: G
authors.initials: G
authors.lastname: Fioravanti
authors.forename: L
authors.initials: L
authors.lastname: Manzoli
authors.forename: C
authors.initials: C
authors.lastname: Finelli
authors.forename: L
authors.initials: L
authors.lastname: Cocco
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D056743:Cyclin D3; D004921:Erythropoietin / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010716:Phosphatidylinositols / Q000378:metabolism; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects*; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: C534696:CCND3 protein, human; D056743:Cyclin D3; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D055544:beta-Globins; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt; D054799:Phospholipase C beta; D051966:Phospholipase C gamma