%0 Journal Article
%T Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia
%J -
%D 2019
%R https://doi.org/10.1038/s41419-019-1593-2
%X Growing evidence indicates that cell adhesion to extracellular matrix (ECM) plays an important role in cancer chemoresistance. Leukemic T cells express several adhesion receptors of the ¦Â1 integrin subfamily with which they interact with ECM. However, the role of ¦Â1 integrins in chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL) is still ill defined. In this study, we demonstrate that interactions of human T-ALL cell lines and primary blasts with three-dimensional matrices including Matrigel and collagen type I gel promote their resistance to doxorubicin via ¦Â1 integrin. The blockade of ¦Â1 integrin with a specific neutralizing antibody sensitized xenografted CEM leukemic cells to doxorubicin, diminished the leukemic burden in the bone marrow and resulted in the extension of animal survival. Mechanistically, Matrigel/¦Â1 integrin interaction enhanced T-ALL chemoresistance by promoting doxorubicin efflux through the activation of the ABCC1 drug transporter. Finally, our findings showed that Matrigel/¦Â1 interaction enhanced doxorubicin efflux and chemoresistance by activating the FAK-related proline-rich tyrosine kinase 2 (PYK2) as both PYK2 inhibitor and siRNA diminished the effect of Matrigel. Collectively, these results support the role of ¦Â1 integrin in T-ALL chemoresistance and suggest that the ¦Â1 integrin pathway can constitute a therapeutic target to avoid chemoresistance and relapsed-disease in human T-ALL
%U https://www.nature.com/articles/s41419-019-1593-2