TY - JOUR AU - Elena Tibaldi, AU - Mario Angelo Pagano, AU - Federica Frezzato, AU - Valentina Trimarco, AU - Monica Facco, AU - Giuseppe Zagotto, AU - Giovanni Ribaudo, AU - Valeria Pavan, AU - Luciana Bordin, AU - Andrea Visentin, AU - Francesca Zonta, AU - Gianpietro Semenzato, AU - Anna Maria Brunati, AU - Livio Trentin, PY - 2017/07/31 Y2 - 2024/03/29 TI - Targeted activation of the SHP-1/PP2A signaling axis elicits apoptosis of chronic lymphocytic leukemia cells JF - Haematologica JA - haematol VL - 102 IS - 8 SE - Articles DO - 10.3324/haematol.2016.155747 UR - https://haematologica.org/article/view/8160 SP - 1401-1412 AB - Lyn, a member of the Src family of kinases, is a key factor in the dysregulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn’s action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia. ER -