Perez-Roger, I. (Ignacio)
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- BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells(American Association for Cancer Research, 2005) Poch, E. (Enric); Montiel-Duarte, C. (Cristina); Martinez-Climent, J.A. (José Ángel); Rifon, J. J. (Jose J.); Arbona, C. (C.); Andreu, E.J. (Enrique José); Perez-Calvo, J. (Javier); Ivorra, C. (Carmen); Prosper-Cardoso, F. (Felipe); Albero, M.P. (M. Pilar); Lledo, E. (Elisa); Perez-Roger, I. (Ignacio)Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G(1) cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27(Kip1) and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27(Kip1) at the level of transcription. We further show that BCR-ABL also regulates p27(Kip1) protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27(Kip1) by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27(Kip1). We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27(Kip1) mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27(Kip1) contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27(Kip1) and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.
- Down-Regulation of hsa-miR-10a in Chronic Myeloid Leukemia CD34+ Cells Increases USF2-Mediated Cell Growth(American Association for Cancer Research, 2008) Vilas, A. (Amaia); Cordeu, L. (Lucía); Jimenez-Velasco, A. (A.); Aparicio, O. (Óscar); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Heiniger, A. (A.); Garate, L. (Leire); Navarro, G. (Germán); Bandres, E. (Eva); Garcia-Foncillas, J. (Jesús); Fortes, P. (Puri); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Perez-Roger, I. (Ignacio); Saez, B. (Borja)MicroRNAs (miRNA) are small noncoding, single-stranded RNAs that inhibit gene expression at a posttranscriptional level, whose abnormal expression has been described in different tumors. The aim of our study was to identify miRNAs potentially implicated in chronic myeloid leukemia (CML). We detected an abnormal miRNA expression profile in mononuclear and CD34+ cells from patients with CML compared with healthy controls. Of 157 miRNAs tested, hsa-miR-10a, hsa-miR-150, and hsa-miR-151 were down-regulated, whereas hsa-miR-96 was up-regulated in CML cells. Down-regulation of hsa-miR-10a was not dependent on BCR-ABL1 activity and contributed to the increased cell growth of CML cells. We identified the upstream stimulatory factor 2 (USF2) as a potential target of hsa-miR-10a and showed that overexpression of USF2 also increases cell growth. The clinical relevance of these findings was shown in a group of 85 newly diagnosed patients with CML in which expression of hsa-miR-10a was down-regulated in 71% of the patients, whereas expression of USF2 was up-regulated in 60% of the CML patients, with overexpression of USF2 being significantly associated with decreased expression of hsa-miR-10a (P = 0.004). Our results indicate that down-regulation of hsa-miR-10a may increase USF2 and contribute to the increase in cell proliferation of CML implicating a miRNA in the abnormal behavior of CML.
- Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells(Nature Publishing Group, 2010) Poch, E. (Enric); Vaquer, J.M. (J.M.); Villanueva, J.J. (J.J.); Andreu, E.J. (Enrique José); Franch, L. (L.); Ivorra, C. (Carmen); Prosper-Cardoso, F. (Felipe); Albero, M.P. (M. Pilar); Aguirre-Ena, X. (Xabier); Perez-Roger, I. (Ignacio)The use of c-abl-specific inhibitors such as Imatinib (IM) or Dasatinib has revolutionized the treatment of chronic myeloid leukemia (CML). However, a significant percentage of patients become resistant to IM. In this report, we have analyzed the possibility of using the proteasome as a molecular target in CML. Our results show that cells that express Bcr-Abl1 are more sensitive to the inhibition of the proteasome with Bortezomib (Btz) than control cells. This treatment reduces the proliferation of Bcr-Abl1- expressing cells, by inactivating NF-jB2 and decreasing the phosphorylation of Rb, eventually leading to an increase in caspase-dependent apoptosis. Furthermore, we show that Btz also induces cell-cycle arrest and apoptosis in cells expressing Bcr-Abl1 mutants that are resistant to IM. These results unravel a new molecular target of Btz, that is the Rb pathway, and open new possibilities in the treatment of CML especially for patients that become resistant to IM because of the presence of the T315I mutation.
- BCR-ABL1-induced expression of HSPA8 promotes cell survival in chronic myeloid leukaemia(Wiley-Blackwell, 2008) Isidro, I. (Isabel); Cordeu, L. (Lucía); Jimenez-Velasco, A. (A.); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Heiniger, A. (A.); Garate, L. (Leire); Ballestar, E. (E.); Andreu, E.J. (Enrique José); Gutierrez, N.C. (Norma C.); Guruceaga, E. (Elizabeth); Esteller, M. (Manel); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Rubio, A. (Ángel); Perez-Roger, I. (Ignacio)In order to determine new signal transduction pathways implicated in chronic myeloid leukaemia (CML), we performed a gene expression profile comparison between CD34+ cells from CML patients and healthy donors. Functional studies were performed using the Mo7e and Mo7e-p210 cell lines. Expression of CCND1 (Cyclin D1), as well as the chaperone HSPA8, which is important for regulation of CCND1, were significantly upregulated in CD34+ CML cells. Upregulation of HSPA8 was dependent, at least in part, on STAT5 (signal transducer and activator of transcrition 5)-dependent transcriptional activation, as demonstrated by chromatin immunoprecipitation. The presence of HSPA8 in the nuclear protein fraction as well as its binding to CCND1 suggests that it may contribute to stabilization of the CCND1/CDK4 complex, which, in turn, may participate in proliferation of CML cells. Treatment of CML cells with the specific HSPA8 inhibitor 15-deoxyspergualin induced inhibition of CML cell viability but did not induce apoptosis. In conclusion, our studies suggest that STAT5-mediated activation of HSPA8 induces nuclear translocation and activation of the CCND1/CDK4 complex leading to increased proliferation of CML cells, deciphering a new pathway implicated in CML and supporting a potential role of chaperone inhibitors in the treatment of CML.