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.
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Authors | 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 |
Journal | Cancer cell
(Cancer Cell)
Vol. 27
Issue 6
Pg. 755-68
(Jun 08 2015)
ISSN: 1878-3686 [Electronic] United States |
PMID | 26058075
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- CXCL12 protein, human
- Chemokine CXCL12
- Cxcl12 protein, mouse
- N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine
- Pyridines
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Topics |
- Animals
- Bone Marrow Cells
(metabolism, pathology)
- Chemokine CXCL12
(antagonists & inhibitors, biosynthesis, genetics)
- Endothelium, Vascular
(metabolism, pathology)
- Female
- Gene Deletion
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, SCID
- Mice, Transgenic
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
(drug therapy, genetics, metabolism, pathology)
- Pyridines
(pharmacology)
- Stromal Cells
(metabolism, pathology)
- Xenograft Model Antitumor Assays
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