Introduction. Inositide signalling pathways are involved in cell growth, differentiation and apoptosis and play a role in the progression of MDS towards AML. In particular, an altered expression of nuclear PI-PLCbeta1 and activated Akt can lead to a deregulation of cell cycle processes, therefore affecting the survival of primary MDS cells. Moreover, we postulated an inverse correlation between PI-PLCbeta1 expression and Akt activation in MDS. Indeed, these processes are critical especially 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. Lenalidomide is currently used in the treatment of del(5q) low-risk MDS patients, to compensate and counteract their ineffective erythropoiesis. In fact, this drug has anti-angiogenic activity, suppresses inflammatory cytokine release, induces the erythroid differentiation and enhances the EPO receptor signalling. The exact molecular mechanisms underlying the effect of Lenalidomide in MDS cells are still unclear, even though it can target signalling pathways playing a role in the maintenance of the balance between apoptosis, proliferation and differentiation, such as PI3K/Akt. Methods. We studied 6 patients diagnosed with del(5q) Low-Risk MDS (IPSS: Low or Int-1) who were given Lenalidomide. We quantified the expression of several genes implicated in inositide signalling, such as PI-PLCbeta1 splicing variants and PIPLCgamma1, as well as Cyclin D3 and Beta-Globin, in order to assess the effect of Lenalidomide on erythropoiesis and cell cycle. 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 BetaGlobin levels increased. Moreover, these subjects also displayed an activation of PI-PLCgamma1, which is associated with PI3K/Akt activation. As for the other 2 cases, patients early discontinued Lenalidomide for adverse events, and for these patients a clinical assessment of Lenalidomide effect was not possible. Conclusions. Our data support the hypothesis of a role for PI-PLCgamma1 activation during Lenalidomide treatment, and confirm the activation of erythropoiesis in responder patients. In fact, Lenalidomide increased the expression of genes specifically associated with erythropoiesis, like Globin genes, in our responder patients. Our results also indicate that both PI-PLCbeta1 splicing variants, as well as Cyclin D3, are not significantly affected by Lenalidomide, whereas PIPLCgamma1 is specifically induced. Taken together, these results point to a specific activation of this pathway during the therapy and possibly pave the way to a larger investigation aiming to assess the role of these pathways in Lenalidomide response.

GENE EXPRESSION OF INOSITIDE-DEPENDENT SIGNAL TRANSDUCTION PATHWAYS IN MDS PATIENTS WITH DEL(5Q) TREATED WITH LENALIDOMIDE / Follo MY; Mongiorgi S; Clissa C; Baccarani M; Paolini S; Curti A; Papayannidis C; Martinelli G; Manzoli L; Finelli C; Cocco L. - In: HAEMATOLOGICA. - ISSN 0390-6078. - STAMPA. - 97:SUPPL 2(2012), pp. S36-S37. (Intervento presentato al convegno XII Congress of the Italian Society of Experimental Hematology tenutosi a ROMA nel 17-19 OTTOBRE 2012).

GENE EXPRESSION OF INOSITIDE-DEPENDENT SIGNAL TRANSDUCTION PATHWAYS IN MDS PATIENTS WITH DEL(5Q) TREATED WITH LENALIDOMIDE

FOLLO, MATILDE YUNG;MONGIORGI, SARA;BACCARANI, MICHELE;PAOLINI, STEFANIA;PAPAYANNIDIS, CRISTINA;MARTINELLI, GIOVANNI;MANZOLI, LUCIA;FINELLI, CARLO;COCCO, LUCIO ILDEBRANDO
2012

Abstract

Introduction. Inositide signalling pathways are involved in cell growth, differentiation and apoptosis and play a role in the progression of MDS towards AML. In particular, an altered expression of nuclear PI-PLCbeta1 and activated Akt can lead to a deregulation of cell cycle processes, therefore affecting the survival of primary MDS cells. Moreover, we postulated an inverse correlation between PI-PLCbeta1 expression and Akt activation in MDS. Indeed, these processes are critical especially 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. Lenalidomide is currently used in the treatment of del(5q) low-risk MDS patients, to compensate and counteract their ineffective erythropoiesis. In fact, this drug has anti-angiogenic activity, suppresses inflammatory cytokine release, induces the erythroid differentiation and enhances the EPO receptor signalling. The exact molecular mechanisms underlying the effect of Lenalidomide in MDS cells are still unclear, even though it can target signalling pathways playing a role in the maintenance of the balance between apoptosis, proliferation and differentiation, such as PI3K/Akt. Methods. We studied 6 patients diagnosed with del(5q) Low-Risk MDS (IPSS: Low or Int-1) who were given Lenalidomide. We quantified the expression of several genes implicated in inositide signalling, such as PI-PLCbeta1 splicing variants and PIPLCgamma1, as well as Cyclin D3 and Beta-Globin, in order to assess the effect of Lenalidomide on erythropoiesis and cell cycle. 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 BetaGlobin levels increased. Moreover, these subjects also displayed an activation of PI-PLCgamma1, which is associated with PI3K/Akt activation. As for the other 2 cases, patients early discontinued Lenalidomide for adverse events, and for these patients a clinical assessment of Lenalidomide effect was not possible. Conclusions. Our data support the hypothesis of a role for PI-PLCgamma1 activation during Lenalidomide treatment, and confirm the activation of erythropoiesis in responder patients. In fact, Lenalidomide increased the expression of genes specifically associated with erythropoiesis, like Globin genes, in our responder patients. Our results also indicate that both PI-PLCbeta1 splicing variants, as well as Cyclin D3, are not significantly affected by Lenalidomide, whereas PIPLCgamma1 is specifically induced. Taken together, these results point to a specific activation of this pathway during the therapy and possibly pave the way to a larger investigation aiming to assess the role of these pathways in Lenalidomide response.
2012
HAEMATOLOGICA
S36
S37
GENE EXPRESSION OF INOSITIDE-DEPENDENT SIGNAL TRANSDUCTION PATHWAYS IN MDS PATIENTS WITH DEL(5Q) TREATED WITH LENALIDOMIDE / Follo MY; Mongiorgi S; Clissa C; Baccarani M; Paolini S; Curti A; Papayannidis C; Martinelli G; Manzoli L; Finelli C; Cocco L. - In: HAEMATOLOGICA. - ISSN 0390-6078. - STAMPA. - 97:SUPPL 2(2012), pp. S36-S37. (Intervento presentato al convegno XII Congress of the Italian Society of Experimental Hematology tenutosi a ROMA nel 17-19 OTTOBRE 2012).
Follo MY; Mongiorgi S; Clissa C; Baccarani M; Paolini S; Curti A; Papayannidis C; Martinelli G; Manzoli L; Finelli C; Cocco L
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/396751
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