Integrin-deficient T cell leukemia accumulates in the central nervous system

Abstract

SummaryT cell acute lymphoblastic leukemia (T-ALL), a devastating childhood cancer, rapidly invades the central nervous system (CNS) and localizes to the meninges. T-ALL is aggressively treated with high-dose, CNS-directed chemotherapy; this regime results in lasting neurotoxicity and in some cases ultimately fails to protect from meningeal relapse. The paucity of knowledge about T-ALL entry and persistence in the CNS has limited the development of targeted therapies for decades. Here, we addressed whether VLA-4 and LFA-1, two integrins that mediate normal T cell entry to the CNS and that have been successfully targeted in patients for treatment of autoimmune disease, were similarly required in T-ALL. In the process, we uncovered an entirely unexpected role for these integrins in CNS disease. Not only were these integrins dispensable for T-ALL to reach the CNS, integrin-deficient T-ALL accumulated in the CNS compared to control T-ALL. Mechanistically, loss of integrins accelerated T-ALL proliferation in the CNS, suggesting that integrin-mediated interactions may promote quiescence in this space and highlighting the importance of niche-specific regulation of disease. Integrin blockade strongly synergized with anti-proliferative chemotherapy to treat CNS disease, indicating that combination therapy might be a powerful therapeutic strategy.