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.
ASJC Scopus subject areas
- Cell Biology