CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance

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. [Display omitted] •T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma•Cxcl12 deletion in vascular endothelial, but not perivascular, cells suppresses disease•Cxcr4 deletion in T-ALL cells after disease onset inhibits leukemia progression•CXCR4 antagonism suppresses human T-ALL in a primary xenograft model Pitt et al. identify a T cell acute lymphoblastic leukemia (T-ALL) niche and show that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Importantly, targeting CXCL12 or its receptor CXCR4 expressed in T-ALL cells reduces tumor growth in murine T-ALL and xenograft models.