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

Department of Pediatrics, Division of Hematology and Oncology, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, United States
Blood (Impact Factor: 10.43). 01/2013; 121(10). DOI: 10.1182/blood-2012-01-406272
Source: PubMed

ABSTRACT The bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells thus contributing to the lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates adhesion of normal and malignant B-cell precursors in BM, and, according to gene expression analyses from 207 children with high-risk pre-B ALL with minimal residual disease, is particularly highly expressed in patients with the poorest outcome. Therefore, we tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. For this purpose, two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 (p210+)-induced murine leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary pre-B ALL). Conditional deletion of alpha4 sensitized leukemia cell to Nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent and alpha4 blockade sensitized primary ALL cells towards chemotherapy. Combination of chemotherapy with an anti-integrin alpha4 antibody, Natalizumab, prolonged survival of NOD/SCID recipients of primary ALL suggesting adjuvant integrin alpha4 inhibition as a novel strategy for pre-B ALL.

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