The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging alpha 4 delta 1-integrin or alpha 5 beta 1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of alpha 4 delta, a truncated alpha 4-integrin with KXGFFKR as the cytoplasmic motif, in alpha 4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of alpha 4-mediated adhesion. The adhesion-independent chemoresistance did not require beta 1-integrin as the heterodimeric pair, since expression of Tac delta, a monomeric nonintegrin transmembrane protein fused to the juxtamembrane KXGFFKR, was sufficient to reproduce the phenomenon. The requirement for integrin-mediated adhesion in stimulation of Akt phosphorylation and activation was bypassed for cells expressing alpha 4 delta and Tac delta. Cells expressing alpha 4 delta and Tac delta exhibited a high influx of extracellular Ca2+, and inhibition of Ca2+ channels with verapamil attenuated the adhesion-independent chemoresistance. Tac delta cells also exhibited greater rates of drug efflux. alpha 4 delta and Tac delta interacted with the Ca2+-binding protein calreticulin, in a manner dependent on the KXGFFKR motif. Adhesion-mediated engagement of alpha 4-integrins promoted an increased calreticulin-alpha 4 association and greater influx of extracellular Ca2+ than in nonadherent cells. The alpha-integrin KXGFFKR motif is involved in adhesion-mediated control of chemoresistance in T cells.