CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance
Pitt, L. A.*, A. N. Tikhonova*, H. Hu, T. Trimarchi, B. King, Y. Gong, M. Sanchez-Martin, A. Tsirigos, D. R. Littman, A. A. Ferrando, S. J. Morrison, D. R. Fooksman, I. Aifantis and S. R. Schwab
Cancer Cell 27(6): 755-768
The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL.