Abstract
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 β1 integrin subfamily with which they interact with ECM. However, the role of β1 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 β1 integrin. The blockade of β1 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/β1 integrin interaction enhanced T-ALL chemoresistance by promoting doxorubicin efflux through the activation of the ABCC1 drug transporter. Finally, our findings showed that Matrigel/β1 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 β1 integrin in T-ALL chemoresistance and suggest that the β1 integrin pathway can constitute a therapeutic target to avoid chemoresistance and relapsed-disease in human T-ALL.
Highlights
Introduction AcuteT cell lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all childhood acute leukemia and 25% of adult ALLs
To examine the implication of the extracellular matrix (ECM) present in the vascular niche and the role of a 3D matrix in T-cell acute lymphoblastic leukemia (T-ALL) chemoresistance, we studied the effect of Matrigel on drug-induced apoptosis in human T-ALL cell lines (CEM, Jurkat, HSB2 and Molt-3), which express variable levels of α integrins and high levels of the β1 integrin chain[17]
The best inhibitory effect was observed in CEM and Jurkat T cell lines where druginduced apoptosis is reduced by 30–40%
Summary
T cell lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all childhood acute leukemia and 25% of adult ALLs. chemotherapy has improved the treatment of T-ALL, the prognosis of drug resistant and relapsed T-ALL remains very poor[1]. Defining the factors promoting T-ALL chemoresistance is critical to improve this prognosis. Normal and malignant hematopoietic cells express several adhesion receptors among which, is the β1 integrin subfamily that mediates their interactions with stromal cells and ECM. The β1 integrins are α/β heterodimeric membrane receptors, which upon ligand binding induce activation of non-receptor tyrosine kinases including focal adhesion kinase (FAK) and its homologous FAK-related proline-rich tyrosine kinase 2 (PYK2) leading to cytoskeletal rearrangements and downstream signaling[4]
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