Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy

Abstract

Bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells, contributing to lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates stromal adhesion of normal and malignant B-cell precursors, and according to gene expression analyses from207 childrenwithminimal residual disease, is highly associatedwith poorest outcome. We tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. Twomodels of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 [p2+01] leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary ALL). Conditional deletion of alpha4 sensitized leukemia cell tonilotinib.Adhesionof primarypre-BALLcellswasalpha4-dependent;alpha4 blockade sensitized primaryALLcells toward chemotherapy.Chemotherapy combinedwith Natalizumab prolonged survival of NOD/SCID recipients of primary ALL, suggesting adjuvant alpha4 inhibition as a novel strategy forpre-B ALL. © 2013 by The American Society of Hematology.