Therapeutic targeting of a9b1 and a4b1 integrins for chemosensitization of drug resistant acute leukaemia

Hematopoietic stem cells (HSC) reside in the bone marrow (BM) niche, which is comprised of multiple cell types that regulate stem cell quiescence, proliferation and differentiation. Several interactions have been identified as important HSC regulators, including CXCR4/SDF-1 and the integrins α9β1 and α4β1, which interact with thrombin cleaved osteopontin (tcOPN). Likewise, leukemic cells also express CXCR4 and α4β1, which allow similar interactions with the BM microenvironment and have previously been shown to mediate leukemic cell quiescence and drug resistance. However, while the role of integrin α9β1 in HSC regulation is well documented, the role of α9β1 in leukemia regulation and drug resistance is not known. Phenotypic screening of patient B-cell precursor ALL (BCP-ALL) BM demonstrated that although all samples expressed CXCR4 and integrin α4β1, only 40% co-expressed α9β1. Notably, co-expression of α9β1 was correlated with poor prognosis and was also associated with chemoresistance in vitro. Using the small molecule integrin antagonist “BOP”, which potently inhibits both α4β1 and α9β1, we show that ALL can be effectively sensitized to chemotherapy in vitro. In addition, synergistic chemosensitization was observed when BOP was used in combination with the CXCR4 antagonist AMD3100. Furthermore, using a patient-derived xenograft model, we demonstrate BOP can effectively bind to minimal residual disease in BM during remission and rapidly dislodges these cells from their protective microenvironment in vivo. In addition, our preliminary results show that co-administration of BOP with AMD3100 reduces ALL burden when used in conjunction with a standard chemotherapy regime consisting of vincristine/dexamethasone/L-asparaginase. Together, our results validate integrin α9β1 as a drug target in ALL and demonstrates that concomitant inhibition of α4β1/α9β1/CXCR4 using BOP plus AMD3100 or other CXCR4 antagonists may be an effective strategy for chemosensitizing drug resistant ALL.