Abstract A06: The chemokine receptor CXCR4 is essential for the maintenance of T cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising in immature T cell progenitors. Despite improved survival rates, relapse remains a major therapeutic obstacle and intensive treatment regimens expose T-ALL patients to serious long-term side-effects. Hence more effective, less toxic treatment options are required. While the localization of leukemia cells determines the course of disease, little is known about T-ALL migration. Upon profiling chemokine receptor expression by T-ALL cells, we observed high surface levels of the CXCL12 receptor, CXCR4. Intravital imaging revealed that T-ALL cells are in direct contact with CXCL12-producing bone marrow stromal cells in vivo. Genetic targeting of CXCR4 in T-ALL cells resulted in a marked reduction of leukemia burden and significantly prolonged survival. Moreover, disruption of CXCR4 signaling with a small molecule inhibitor severely impaired T-ALL progression in mouse and human xenograft models of the disease. We found that CXCR4 promotes c-Myc expression, which is required in leukemia initiating cells. Given the relatively subtle role for CXCR4 in normal developing T cells, CXCR4 inhibition to our knowledge has not been proposed as a therapy for T cell malignancies. Our data strongly suggest that targeting CXCR4 could be a promising strategy for combating T-ALL. Citation Format: Lauren A. Pitt, Anastasia N. Tikhonova, Thomas Trimarchi, Bryan King, Hai Hu, Yixiao Gong, Aris Tsirigos, Marta Sanchez-Martin, Dan R. Littman, Adolfo Ferrando, Sean J. Morrison, David R. Fooksman, Iannis Aifantis, Susan Schwab. The chemokine receptor CXCR4 is essential for the maintenance of T cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A06.