Imatinib mesylate suppresses T-cell activation through inhibition of Lck/Zap-70 signaling: Evidence for a role in herpes zoster reactivation in CML patients

1241 Imatinib mesylate (IM) inhibits the BCR-ABL oncogene and effectively controls BCR-ABL (+) leukemias. This drug is one of the first and most successful applications of targeted therapy where minimal interference with unintended targets reduces drug toxicity. However, tyrosine kinases other than BCR-ABL are inhibited by IM; some exploited for therapeutic purposes in other disease. In CML patients receiving IM herpes zoster episodes were noted in a percentage of patients that had not been seen with other forms of CML therapy. The risk of herpes zoster reactivation in CML patient receiving IM was much higher than the general age-matched population, suggesting a link between IM therapy and herpes zoster episodes. In IM treated CML patients T-cell cytokine levels (IFN-gamma, IL-2) were significantly reduced, suggesting an impairment in T-cell function. Treatment of Jurkat T-cells with IM reduced tyrosine phosphorylation and cytokine expression without inducing apoptosis. In vitro studies with purified Lck and Zap-70 kinases demonstrated that Lck was inhibited at IM concentrations that are clinically achievable. Only Lck and Lyn kinase in the src family demonstrated sensitivity to IM-mediated kinase inhibition with IC50 values of 5.1 and 3.8 microM, respectively. In CML patients we detected suppression of Lck/Zap-70 signaling (p-LAT) following IM therapy. Signaling and cytokine expression were also inhibited by IM in T-cells derived from normal donors. These results suggest that IM suppresses T-cell activation through inhibition of Lck/Zap-70 signaling and may play a role in the inability of CML patients receiving IM to prevent the reactivation of varicella zoster virus infection