Baccarani, Michele

Bosi, Costanza

Chiarini, Francesca

Clissa, Cristina

Cocco, Lucio

Finelli, Carlo

Follo, Matilde Y.

Manzoli, Lucia

Martelli, Alberto M.

Martinelli, Giovanni

Mongiorgi, Sara

Stoyanova, Mariana

Firenze University Press: E-Journals

IJAE Vol. 115, n. 1/2 (Supplement), 2010
69
Effect of combination of azacitidine and valproic acid 
on PI-PLCbeta1 signaling in high-risk myelodysplastic 
syndromes
Matilde Y. Follo1, Sara Mongiorgi1, Carlo Finelli2, Cristina Clissa2, Mariana Stoyanova2, Costanza Bosi3, 
Francesca Chiarini1, Michele Baccarani2, Alberto M. Martelli1, Giovanni Martinelli2, Lucia Manzoli1, 
Lucio Cocco1
1 Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Italy
2 Institute of Hematology and Medical Oncology “L. e A. Seràgnoli”, University of Bologna, Italy 
3 Hematology Unit, Ospedale Civile di Piacenza, Piacenza, Italy 
4 Istituto per i Trapianti d’Organo e l’Immunocitologia del C.N.R., Sezione di Bologna c/o I.O.R., Bologna, Italy 
Nuclear inositides are involved in several processes, including DNA repair, transcrip-
tion regulation and RNA dynamics in normal and neoplastic conditions. Namely, nuclear 
phosphoinositide-phospholipase C (PI-PLC) beta1 plays an essential role in cell cycle 
regulation, mainly targeting cyclin D3. Moreover, PI-PLCbeta1 has been linked to the 
pathogenesis of myelodysplastic syndromes (MDS), i.e. clonal hematopoietic stem cell 
disorders characterized by ineffective hematopoiesis in one or more of the lineages of the 
bone marrow. Frequently, MDS result in a slow decrease in blood cell counts, but they 
may also show a worsening severe cytopenia or, in about 30% of all the cases, evolve into 
Acute Myeloid Leukemia (AML). Currently, azacitidine (AZA), a DNA methyltransferase 
inhibitor, is used to prolong survival and delay the MDS evolution into AML, alone or in 
combination with the histone deacetylase inhibitor valproic acid (VPA). 
In this study we analyzed the effect of AZA and VPA on inositide signaling pathways 
on high-risk MDS patients receiving AZA (75 mg/sqm/die SC for 7 days/28 days) and 
VPA (600-1.500 mg/die orally). We also studied the effect of AZA and VPA on HL60 cell 
line, which shows a hyper-methylation of PI-PLCbeta1 promoter and is affected by AZA 
treatment. Our results demonstrate that VPA enhances the effect of AZA on inositide sig-
naling pathways, increasing the demethylation effect induced by AZA on PI-PLCbeta1 
promoter and inducing gene and protein expression of other critical molecules. Taken 
together, our findings demonstrate for the first time that, at a molecular level, AZA and 
VPA can modulate key molecules of inositide signaling pathways, thus hinting at a role 
for these molecules as therapeutic targets for high-risk MDS. 
Key words
PI-PLCbeta1, Nucleus, Myelodysplastic Syndromes


Effect of combination of azacitidine and valproic acid on PI-PLCbeta1 signaling in high-risk myelodysplastic syndromes

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Effect of combination of azacitidine and valproic acid on PI-PLCbeta1 signaling in high-risk myelodysplastic syndromes

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