@article{Laia Rosich_Ifigènia Saborit-Villarroya_Mónica López-Guerra_Sílvia Xargay-Torrent_Arnau Montraveta_Marta Aymerich_Neus Villamor_Elias Campo_Patricia Pérez-Galán_Gaël Roué_Dolors Colomer_2013, place={Pavia, Italy}, title={The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells}, volume={98}, url={https://haematologica.org/article/view/6837}, DOI={10.3324/haematol.2013.088849}, abstractNote={Phosphatidylinositol-3-kinase pathway is constitutively activated in chronic lymphocytic leukemia mainly due to microenvironment signals, including stromal cell interaction and CXCR4 and B-cell receptor activation. Because of the importance of phosphatidylinositol-3-kinase signaling in chronic lymphocytic leukemia, we investigated the activity of the NVP-BKM120, an orally available pan class I phosphatidylinositol-3-kinase inhibitor. Sensitivity to NVP-BKM120 was analyzed in chronic lymphocytic leukemia primary samples in the context of B-cell receptor and microenvironment stimulation. NVP-BKM120 promoted mitochondrial apoptosis in most primary cells independently of common prognostic markers. NVP-BKM120 activity induced the blockage of phosphatidylinositol-3-kinase signaling, decreased Akt and FoxO3a phosphorylation leading to concomitant Mcl-1 downregulation and Bim induction. Accordingly, selective knockdown of <em>BIM</em&gt; rescued cells from NVP-BKM120-induced apoptosis, while the kinase inhibitor synergistically enhanced the apoptosis induced by the BH3-mimetic ABT-263. We also found NVP-BKM120 to inhibit B-cell receptor- and stroma-dependent Akt pathway activation, thus sensitizing chronic lymphocytic leukemia cells to bendamustine and fludarabine. Furthermore, NVP-BKM120 down-regulated secretion of chemokines after B-cell receptor stimulation and inhibited cell chemotaxis and actin polymerization upon CXCR4 triggering by CXCL12. Our findings establish that NVP-BKM120 effectively inhibits the phosphatidylinositol-3-kinase signaling pathway and disturbs the protective effect of the tumor microenvironment with the subsequent apoptosis induction through the Akt/FoxO3a/Bim axis. We provide here a strong rationale for undertaking clinical trials of NVP-BKM120 in chronic lymphocytic leukemia patients alone or in combination therapies.}, number={11}, journal={Haematologica}, author={Laia Rosich and Ifigènia Saborit-Villarroya and Mónica López-Guerra and Sílvia Xargay-Torrent and Arnau Montraveta and Marta Aymerich and Neus Villamor and Elias Campo and Patricia Pérez-Galán and Gaël Roué and Dolors Colomer}, year={2013}, month={Nov.}, pages={1739-1747} }