Background: The activation of inositide signalling pathways, such as Akt/mTOR, has been demonstrated in high-risk MDS. Akt also binds PI-PLCgamma1, leading to a deregulation of stem cell proliferation, differentiation and apoptosis. These processes are critical in 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. Introduction: 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. Lenalidomide also shows anti-angiogenic activity and suppresses inflammatory cytokine release. The exact molecular mechanisms underlying the effect of Lenalidomide in MDS cells are still unclear, even though it has been demonstrated that in Lenalidomide-sensitive del(5q) cell lines, Akt phosphorylation is inhibited. Purpose: We studied the effect of Lenalidomide on nuclear inositide signalling pathways in del(5q) low-risk MDS. Materials and Methods: We studied the expression of inositide signalling molecules in 6 patients diagnosed with del(5q) MDS (IPSS: Low or Int-1) who were given Lenalidomide. Given the limited number of cells, we quantified the expression of Akt and PI-PLCgamma1 in 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. Results: In our case series, 4 out of 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 PIPLCgamma1 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. Conclusions: 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 the 5q+ clone. Therefore, it is conceivable that Lenalidomide strengthens the proliferation of the 5q+ clone, whilst the del(5q) clone undergoes an apoptotic process, allowing the restoration of the normal erythropoiesis. This is extremely important, not only for 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;MONGIORGI, SARA;PAOLINI, STEFANIA;QUARANTA, MARILISA;MARTINELLI, GIOVANNI;MANZOLI, LUCIA;COCCO, LUCIO ILDEBRANDO;FINELLI, CARLO
2013

Abstract

Background: The activation of inositide signalling pathways, such as Akt/mTOR, has been demonstrated in high-risk MDS. Akt also binds PI-PLCgamma1, leading to a deregulation of stem cell proliferation, differentiation and apoptosis. These processes are critical in 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. Introduction: 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. Lenalidomide also shows anti-angiogenic activity and suppresses inflammatory cytokine release. The exact molecular mechanisms underlying the effect of Lenalidomide in MDS cells are still unclear, even though it has been demonstrated that in Lenalidomide-sensitive del(5q) cell lines, Akt phosphorylation is inhibited. Purpose: We studied the effect of Lenalidomide on nuclear inositide signalling pathways in del(5q) low-risk MDS. Materials and Methods: We studied the expression of inositide signalling molecules in 6 patients diagnosed with del(5q) MDS (IPSS: Low or Int-1) who were given Lenalidomide. Given the limited number of cells, we quantified the expression of Akt and PI-PLCgamma1 in 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. Results: In our case series, 4 out of 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 PIPLCgamma1 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. Conclusions: 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 the 5q+ clone. Therefore, it is conceivable that Lenalidomide strengthens the proliferation of the 5q+ clone, whilst the del(5q) clone undergoes an apoptotic process, allowing the restoration of the normal erythropoiesis. This is extremely important, not only for MDS pathogenesis, but also for the development of innovative targeted therapies.
LEUKEMIA RESEARCH
S28
S28
LEUKEMIA RESEARCH
M.Y. Follo; S. Mongiorgi; C. Clissa; M. Stoyanova; S. Paolini; M. Quaranta; G. Martinelli; L. Manzoli; C. Cocco; C. Finelli
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/395995
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