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

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.
AuthorsLauren 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
JournalCancer cell (Cancer Cell) Vol. 27 Issue 6 Pg. 755-68 (Jun 08 2015) ISSN: 1878-3686 [Electronic] United States
PMID26058075 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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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