Abstract
Integrin α4 blockade enhances the sensitivity of resistant pre-B ALL cells to chemotherapy.
Major finding: Integrin α4 blockade enhances the sensitivity of resistant pre-B ALL cells to chemotherapy.
Mechanism: Inactivation of integrin α4 impairs ALL cell–stromal adhesion required for cell survival.
Impact: Combined treatment with natalizumab and chemotherapy prolongs survival in mice with ALL.
Adhesion to stromal proteins in the bone marrow protects acute lymphoblastic leukemia (ALL) cells from cytotoxic chemotherapy, contributing to drug resistance and tumor relapse. This adhesion is mediated in part by integrin α4, which, together with integrin β1, interacts with receptors such as vascular cell adhesion molecule 1 (VCAM1) in the bone marrow to promote ALL cell survival. Hsieh and colleagues found that high integrin α4 expression on pre-B ALL cells was correlated with decreased overall survival in a cohort of 207 patients with high-risk ALL, and investigated whether blockade of integrin α4-dependent adhesion modulated the drug response of ALL cells. Genetic ablation of the gene encoding integrin α4, Itga4, in BCR–ABL-positive murine leukemia cells resulted in decreased adhesion to VCAM1, loss of colony forming ability, and reduced cell viability following treatment with chemotherapeutic agents in vitro. Furthermore, mice engrafted with Itga4-deficient leukemia cells exhibited improved response to nilotinib and prolonged survival compared with recipients of Itga4-expressing cells, indicating that integrin α4 inactivation increases the sensitivity of ALL cells to chemotherapy. As an alternative strategy, integrin α4 function was pharmacologically inhibited in patient-derived drug resistant pre-B ALL cells using natalizumab, a humanized integrin α4-targeted monoclonal antibody that is clinically approved for the treatment of autoimmune diseases. Similar to Itga4 deletion, natalizumab impaired leukemia cell adhesion to VCAM1 and sensitized primary ALL cells to chemotherapy. Additionally, combined administration of chemotherapy and natalizumab significantly enhanced the survival of leukemia-bearing mice. These findings identify integrin α4 as a critical regulator of drug sensitivity and suggest adjuvant treatment with anti-integrin α4 antibodies as a potential strategy to overcome chemotherapy resistance in patients with pre-B ALL.
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