Direct effect of dasatinib on signal transduction pathways associated with a rapid mobilization of cytotoxic lymphocytes

It has been shown that an increase in cytotoxic lymphocyte counts in the peripheral blood occurs rapidly after taking dasatinib, but the underlying mechanism is not yet elucidated. To investigate the influence of dasatinib on signal transduction pathways, we investigated the changes in JAK-STAT, mitogen-activated protein kinase (MAPK), and Akt in cytotoxic lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), before and after dasatinib treatment in chronic myeloid leukemia patients. Among a total of 30 patients, 18 were treated with dasatinib, nine with imatinib, and three with nilotinib. At constitutive levels, the expression of phosphorylated proteins, pSTAT1, pSTAT3, and PERK in NK cells and pSTAT3 in CTLs, was significantly higher in dasatinib-treated patients. Among the patients evaluated, only dasatinib-treated patients showed inhibition of multiple signaling pathways after taking a tyrosine kinase inhibitor. The magnitude of PERK and pAKT inhibition was closely associated with an increase in NK cells and CTLs, respectively, after taking a tyrosine kinase inhibitor. Those responses were more evident in patients with cytomegalovirus IgG positivity. In this study, we demonstrated for the first time, the influence of dasatinib on cell events in cytotoxic lymphocytes in vivo and explained the possible underlying mechanism that results in lymphocyte mobilization after dasatinib treatment.