Therapeutic target of small GTPase for Ph positive leukemias

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PECAM-1(CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing surface glycoprotein expressed in various hematopoietic cells and plays roles in regulation of adhesion and migration of hematopoietic progenitor cells. PECAM-1 has also been implicated in activation of the Ras family GTPase Rap1 and in regulation of apoptosis. We previously reported that BCR/ABL activates the Rap1/B-Raf signaling pathway to regulate proliferation and integrin-mediated adhesion of Ph+ leukemic cells. In the present study, we demonstrate that PECAM-1 was tyrosine phosphorylated in ITIM in various BCR/ABL-expressing cells including primary CML and Ph+ ALL cells, which was inhibited by imatinib or dasatinib and was more prominently observed in cells expressing the imatinib-resistant E255K or T315I mutant. Transient expression experiments further revealed that ITIM in PECAM-1 was tyrosine phosphorylated by BCR/ABL or Lyn and was dephosphorylated by SHP2. Overexpression of PECAM-1 augmented BCR/ABL-mediated activation of Rap1/MEK/Erk pathway and enhanced chemotaxis induced by SDF-1, which also induced tyrosine phosphorylation of PECAM-1. Finally, PECAM-1 specifically inhibited apoptosis induced in K562 cells by imatinib or dasatinib but not that by the Bcl2 family antagonist ABT-737. These data suggest that PECAM-1 may play a role in regulation of apoptosis and migration of BCR/ABL-expressing cells to modulate their imatinib sensitivity and would be a possible candidate for therapeutic target in Ph+ leukemias.