TY - JOUR
T1 - CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance
AU - Pitt, Lauren A.
AU - Tikhonova, Anastasia N.
AU - Hu, Hai
AU - Trimarchi, Thomas
AU - King, Bryan
AU - Gong, Yixiao
AU - Sanchez-Martin, Marta
AU - Tsirigos, Aris
AU - Littman, Dan R.
AU - Ferrando, Adolfo A.
AU - Morrison, Sean J.
AU - Fooksman, David R.
AU - Aifantis, Iannis
AU - Schwab, Susan R.
N1 - Funding Information:
We would like to thank the members of the S.R.S. and I.A. laboratories for helpful discussions throughout the duration of the project. We are grateful to Dr. A. Heguy and the NYU Genome Technology Center (supported in part by a NIH/NCI grant P30CA016087-30) for assistance with sequencing experiments. We are grateful to Dr. C. Loomis and Dr. Z. Dewan from the NYU Histopathology Core (supported by Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center) for assistance with tissue sectioning and Dr. Cynthia Liu for expert pathological advice. We thank M. Cammer from the NYU Microscopy Core for assistance with image analysis. D.R.F. is supported by a Scholars Award from the Alexandrine and Alexander L. Sinsheimer Fund and is also supported by the Albert Einstein Cancer Center (P30CA013330). I.A. is supported by NIH (1RO1CA133379, 1RO1CA105129, 1RO1CA149655, 5RO1CA173636, 5RO1CA169784, and 1RO1GM088847). I.A. is also supported by the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society (TRP#6340-11, LLS#6373-13), The Chemotherapy Foundation, the Irma T. Hirschl Trust, The V Foundation for Cancer Research, and the St. Baldrick’s Foundation. A.N.T. is a Leukemia & Lymphoma Society Special Fellow. T.T. is supported by NIH training grant 5T32CA009161-37. I.A. is a Howard Hughes Medical Institute Early Career Scientist. S.R.S. is supported by NIH (5R01AI085166 and P30CA016087), the Children’s Leukemia Research Association, and the Dana Foundation.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/6/8
Y1 - 2015/6/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccell.2015.05.002
DO - 10.1016/j.ccell.2015.05.002
M3 - Article
C2 - 26058075
AN - SCOPUS:84930583383
SN - 1535-6108
VL - 27
SP - 755
EP - 768
JO - Cancer Cell
JF - Cancer Cell
IS - 6
ER -