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Cancer Cell. 2015 Jun 8;27(6):755-68. doi: 10.1016/j.ccell.2015.05.002.

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

Author information

1
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
2
Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
3
Institute for Cancer Genetics, Department of Pathology and Department of Pediatrics, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA.
4
Howard Hughes Medical Institute and Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
5
Howard Hughes Medical Institute and Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 131, Bronx, NY 10461, USA.
7
Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address: iannis.aifantis@nyumc.org.
8
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address: susan.schwab@med.nyu.edu.

Abstract

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.

PMID:
26058075
PMCID:
PMC4461838
DOI:
10.1016/j.ccell.2015.05.002
[Indexed for MEDLINE]
Free PMC Article

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