VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux

SIMPLE SUMMARY: Cellular adhesion plays an important role in the development of resistance to chemotherapy (chemoresistance) that represents a major hurdle in the treatment of leukemia and which is a major cause for patient relapse. In this study, we evaluated if cell adhesion to the molecule VCAM-1, which is present in the leukemia microenvironment, can favour the chemoresistance of T acute lymphoblastic leukemia (T-ALL). Our results showed that adhesion of T-ALL cells to VCAM-1 via their receptor VLA-4 induces the resistance of T-ALL cells to doxorubicin by activating the signaling protein PYK2 but not FAK. VLA-4/PYK2 signaling did so by inducing the efflux of doxorubicin. However, adhesion of T-ALL cells to fibronectin via the receptor VLA-5 did not activate PYK2 and had no effect on doxorubicin resistance. These findings suggest that targeting the VLA-4/PYK2 pathway could overcome T-ALL chemoresistance and reduce the risk of patient relapse. ABSTRACT: Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse.