Strategic Role of Nuclear Inositide Signalling in Myelodysplastic Syndromes Therapy

Author(s): Lucia Manzoli, Sara Mongiorgi, Cristina Clissa, Carlo Finelli, Anna Maria Billi, Alessandro Poli, Marilisa Quaranta, Lucio Cocco, Matilde Y. Follo

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 14 , Issue 11 , 2014

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Nuclear inositide signalling is implicated in normal and pathological cell proliferation and differentiation in several distinct models. Among the key molecules of nuclear inositide pathways, phosphoinositide-phospholipase (PI-PLC) C β1 is essential for regulating hematopoiesis, particularly along myeloid and erythroid lineage. Moreover, Akt activation is associated with protein synthesis, via mTOR pathway, and with erythroid induction, through PI-PLCγ1 activation. Myelodysplastic syndromes (MDS) are a series of heterogeneous diseases characterized by ineffective hemopoiesis, with a variable risk of evolution into acute myeloid leukemia (AML). Therapeutic approaches for MDS include demethylating agents, such as azacitidine, aiming at reducing cell proliferation, and erythropoietin, useful for sustaining a normal erythropoiesis. In the last few years, a role for nuclear inositide signalling as a therapeutic target in MDS has been disclosed, in that PI-PLCβ1 increase is associated with azacitidine responsiveness, even when this drug is used in combination with other agents, and Akt is specifically activated in MDS at higher risk of AML evolution. On the other hand, recent data demonstrated that inositide signalling can also be involved in erythroid therapy, given the inhibitory effect of erythropoietin on PI-PLCβ1 and the activation of Akt/PI-PLCγ1 pathway, following the administration of erythropoietin. Here, we review the strategic role of nuclear inositide signalling in MDS, in pathogenesis and therapy.

Keywords: Akt, azacitidine, erythropoietin, erythroid differentiation, myelodysplastic syndromes, myeloid differentiation, nuclear inositides, phospholipase Cβ1.

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Article Details

Year: 2014
Page: [873 - 883]
Pages: 11
DOI: 10.2174/1389557514666141013125936
Price: $65

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