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Our results showed uctuating PIP2 levels, which were inversely related to the amount of PI-PLCb-1 and directly related to the levels of activated Akt, indicating a possible correlation between these two molecules. In fact, as Figure 2 shows, when the patient displayed high-levels of activated Akt, for example before the beginning of the treatment, he demonstrated low-levels of PI-PLCb-1. On the contrary, when the expression of PI-PLCb-1 reached its highest level, that corresponded to the lowest levels of activated Akt. These molecular ndings, together with the clinical data of the patient, are consistent with the hypothesis that in high-risk MDS cases azacitidine might have a direct effect on PI-PLCb-1, which could play an essential role in MDS, as well as activated Akt, whose pathways are correlated to the imbalance of the apoptotic processes in MDS cells. Moreover, it is reasonable to hypothesize that the balance between these two molecules could be directly related to PIP2 levels.
To our knowledge, this is the rst time that a correlation between azacitidine treatment and a lipid signaling pathway has been described; furthermore, this is the rst report of a possible direct association between PI-PLCb-1 and activated Akt levels. Future investigations are needed to fully understand the molecular mechanisms underlying the pathogenesis of the disease and the role of azacitidine on these signaling pathways. Nevertheless, our ndings have signicance for high-risk MDS patients, since the altered expression of nuclear PI-PLCb-1 and the amount of activated Akt could be involved in a deregulation of the cell cycle and negatively inuence cell apoptosis processes, thereby affecting the survival of primary MDS cells. Taken together, our data contribute to the further clarication of the therapeutic activity of azacitidine in high-risk MDS. Moreover, these results might pave the way for new therapeutic approaches in these patients, as the quantication of the expression of PI-PLCb-1 and levels of activated Akt could represent an attractive new predictive factor for the responsiveness to azacitidine treatments.
Acknowledgements
This work was supported by CARISBO Foundation, Bologna, Italy and Italian Association for Cancer Research (AIRC).
MY Follo1, C Finelli2, C Bosi2,3, G Martinelli2, S Mongiorgi1, M Baccarani2, L Manzoli1, WL Blalock1, AM Martelli1,4 and
L Cocco1
1Cellular Signalling Laboratory, Department of Anatomical Sciences, University...