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PECAM-1 (CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containingsurface glycoprotein expressed on various hematopoietic cells as well as on endothelialcells. PECAM-1 has been shown to play roles in regulation of adhesion, migrationand apoptosis. The BCR/ABL fusion tyrosine kinase is expressed in chronic myeloidleukemia and Philadelphia-positive (Ph+) acute lymphoblastic leukemia cells, andits inhibition by the clinically used tyrosine kinase inhibitors imatinib or dasatinibinduces apoptosis of these cells. In the present study, we demonstrate that PECAM-1is tyrosine phospho-rylated in its ITIM motifs in various BCR/ABL-expressing cellsincluding primary leukemia cells. Studies using imatinib and dasatinib as wellas transient expression experiments in 293T cells revealed that PECAM-1 was phosphorylateddirectly by BCR/ABL, which was enhanced by the imatinib-resistant E255K and T315Imutations, or partly by the Src family tyrosine kinases, including Lyn, whichwere activated dependently or independently on BCR/ABL. We also demonstrate byusing a substrate trapping mutant of SHP2 that tyrosine phosphorylated PECAM-1binds SHP2 and is a major substrate for this tyrosine phosphatase in BCR/ABL-expressingcells. Overexpression of PECAM-1 in BCR/ABL-expressing cells, including K562 humanleukemia cells, enhanced cell adhesion and partially inhibited imatinib-inducedapoptosis involving mitochondria depolarization and caspase-3 cleavage, at leastpartly, in an ITIM-independent manner. These data suggest that PECAM-1 may playa role in regulation of apoptosis as well as adhesion of BCR/ABL-expressing cellsto modulate their imatinib sensitivity and would be a possible candidate for therapeutictarget in Ph+ leukemias.

PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positive leukemia cells