EFFECT OF LENALIDOMIDE ON INOSITIDE-DEPENDENT SIGNAL TRANSDUCTION PATHWAYS

Lenalidomide (Len) has proven effectiveness in 70-80% of low-risk MDS cases with del(5q), resulting in transfusion-independence, and inducing a rise hemoglobin levels, suppression of the 5q clone and improvement of bone marrow morphologic features. In del(5q) MDS, Len might suppress the dysplastic clone, while in non-del(5q) it may promote effective erythropoiesis, via activation of EPO signalling, which in turn is associated with PI-PLCgamma1 pathway. However, the exact molecular mechanisms underlying the effect of Len in MDS cells are still unclear. Interestingly, Len targets the phosphatase PP2A, whose gene is located in the common deleted region and which usually targets Akt. Indeed, Akt-dependent pathways are critical in low-risk MDS, which display a marked apoptosis and a low proliferation rate. Recently, our group showed that inositide signalling pathways are involved in the MDS progression to AML. In particular, we demonstrated not only that MDS can show alterations on PI-PLCbeta1 and Akt pathways, but also that Akt is inversely correlated with PI-PLCbeta1, therefore affecting MDS cell survival and differentiation. Here, we report on a patient affected by MDS who was successfully treated with Len. The patient, a 58-year old female, was diagnosed with Refractory Anemia (IPSS: Low) and was given only supportive care before undergoing Len treatment. Shortly after the beginning of the therapy, in 2009, the patient showed a clinical favorable response to Len, and subsequently achieved complete hematologic and cytogenetic remission. To assess the molecular effects of Len on inositide signalling pathways, we analyzed the expression of critical genes involved in cell proliferation and differentiation, i.e. PI-PLCbeta1 and its downstream target Cyclin D3, as well as PI-PLCgamma1, which is linked with EPO signalling and Akt activation. That is why ongoing analyses are also trying to examine the effect of Len on Akt, and the correlation between Len and the expression of other genes specifically associated with erythropoiesis, like Globin genes. So far, our results indicate that both PI-PLCbeta1 and Cyclin D3 are not significantly affected by Len, whereas PI-PLCgamma1 is specifically induced. Consequently, these findings hint at a specific activation of PI-PLCgamma1 signalling following Len treatment, and possibly pave the way to further investigations aiming to better understand the role of these pathways in the mechanism of action of Len in del(5q) MDS