Lenalidomide is currently used in the treatment of del(5q) low-risk MDS patients, where it may suppress the del(5q) clone and restore a normal erythropoiesis. The exact molecular mechanisms underlying the effect of Lenalidomide in MDS cells are still unclear, although Akt phosphorylation is inhibited in Lenalidomide-sensitive del(5q) cell lines. The activation of Akt/mTOR or Akt/PI-PLCgamma1 pathways have been demonstrated in high-risk MDS, thus affecting stem cell proliferation, differentiation and apoptosis, i.e. critical processes for low-risk MDS, that usually show a marked apoptosis and a low proliferation rate, which can be rapidly reversed, thus leading to a worse clinical Status. Here we studied the effect of Lenalidomide on inositide signalling pathways in 6 patients diagnosed with del(5q) MDS (IPSS: Low or Int-1) who were given Lenalidomide. Given the limited number of cells, we analyzed bone marrow total mononuclear cells. As for Akt phosphorylation, we analyzed its localization along with RPS14, in order to specifically detect the del(5q) clone. Moreover, by Real-Time PCR analyses, we assessed the expression of Beta-Globin, to evaluate the effect of the drug on erythropoiesis. In our case series, 4/6 del(5q) low-risk MDS patients responded to Lenalidomide and showed an activation of erythropoiesis, in that Beta-Globin levels increased, as compared with baseline. Moreover, these subjects also displayed an activation of PI-PLCgamma1 and Akt. Interestingly, Akt resulted to be specifically phosphorylated in cells not showing the 5q deletion, hinting at a clonal activation of this pathway. The 2 non responder patients early discontinued Lenalidomide for adverse events, and for these patients neither a clinical assessment of Lenalidomide effect, nor a molecular analysis, were possible. Our data show Akt/PI-PLCgamma1 activation during Lenalidomide treatment, and confirm the activation of erythropoiesis in responder patients. In addition, our results indicate that Akt is specifically phosphorylated in normal cells without del(5q). Therefore, it is conceivable that Lenalidomide may act not only by inducing apoptosis in clonal del(5q) cells, but also by enhancing the proliferation of normal non clonal cells, as described in non del(5q) MDS (Ebert, 2008), allowing the restoration of the normal erythropoiesis. This finding might be useful not only for understanding MDS pathogenesis, but also for the development of innovative targeted therapies.

CLONAL ACTIVATION OF AKT IN LOW-RISK MDS PATIENTS WITH DEL(5Q) TREATED WITH LENALIDOMIDE

FOLLO, MATILDE YUNG;CLISSA, CRISTINA;MONGIORGI, SARA;STOYANOVA, MARIANA;PAOLINI, STEFANIA;QUARANTA, MARILISA;STANZANI, MARTA;MARTINELLI, GIOVANNI;MANZOLI, LUCIA;COCCO, LUCIO ILDEBRANDO;FINELLI, CARLO
2013

Abstract

Lenalidomide is currently used in the treatment of del(5q) low-risk MDS patients, where it may suppress the del(5q) clone and restore a normal erythropoiesis. The exact molecular mechanisms underlying the effect of Lenalidomide in MDS cells are still unclear, although Akt phosphorylation is inhibited in Lenalidomide-sensitive del(5q) cell lines. The activation of Akt/mTOR or Akt/PI-PLCgamma1 pathways have been demonstrated in high-risk MDS, thus affecting stem cell proliferation, differentiation and apoptosis, i.e. critical processes for low-risk MDS, that usually show a marked apoptosis and a low proliferation rate, which can be rapidly reversed, thus leading to a worse clinical Status. Here we studied the effect of Lenalidomide on inositide signalling pathways in 6 patients diagnosed with del(5q) MDS (IPSS: Low or Int-1) who were given Lenalidomide. Given the limited number of cells, we analyzed bone marrow total mononuclear cells. As for Akt phosphorylation, we analyzed its localization along with RPS14, in order to specifically detect the del(5q) clone. Moreover, by Real-Time PCR analyses, we assessed the expression of Beta-Globin, to evaluate the effect of the drug on erythropoiesis. In our case series, 4/6 del(5q) low-risk MDS patients responded to Lenalidomide and showed an activation of erythropoiesis, in that Beta-Globin levels increased, as compared with baseline. Moreover, these subjects also displayed an activation of PI-PLCgamma1 and Akt. Interestingly, Akt resulted to be specifically phosphorylated in cells not showing the 5q deletion, hinting at a clonal activation of this pathway. The 2 non responder patients early discontinued Lenalidomide for adverse events, and for these patients neither a clinical assessment of Lenalidomide effect, nor a molecular analysis, were possible. Our data show Akt/PI-PLCgamma1 activation during Lenalidomide treatment, and confirm the activation of erythropoiesis in responder patients. In addition, our results indicate that Akt is specifically phosphorylated in normal cells without del(5q). Therefore, it is conceivable that Lenalidomide may act not only by inducing apoptosis in clonal del(5q) cells, but also by enhancing the proliferation of normal non clonal cells, as described in non del(5q) MDS (Ebert, 2008), allowing the restoration of the normal erythropoiesis. This finding might be useful not only for understanding MDS pathogenesis, but also for the development of innovative targeted therapies.
HAEMATOLOGICA
40
40
Follo MY; Clissa C; Mongiorgi S; Stoyanova M; Paolini S; Quaranta M; Stanzani M; Martinelli G; Manzoli L; Cocco L; Finelli C
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/416979
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