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

Lauren A. Pitt, Anastasia N. Tikhonova, Hai Hu, Thomas Trimarchi, Bryan King, Yixiao Gong, Marta Sanchez-Martin, Aris Tsirigos, Dan R. Littman, Adolfo A. Ferrando, Sean J. Morrison, David R. Fooksman, Iannis Aifantis, Susan R. Schwab

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

The role of the microenvironment in Tcell 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 invivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL.

Original languageEnglish (US)
Pages (from-to)755-768
Number of pages14
JournalCancer Cell
Volume27
Issue number6
DOIs
StatePublished - Jun 8 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Pitt, L. A., Tikhonova, A. N., Hu, H., Trimarchi, T., King, B., Gong, Y., Sanchez-Martin, M., Tsirigos, A., Littman, D. R., Ferrando, A. A., Morrison, S. J., Fooksman, D. R., Aifantis, I., & Schwab, S. R. (2015). CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance. Cancer Cell, 27(6), 755-768. https://doi.org/10.1016/j.ccell.2015.05.002