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

doi:10.1016/j.ccell.2015.05.002

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

Pathology

Research output: Contribution to journal › Article › peer-review

200 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 language	English (US)
Pages (from-to)	755-768
Number of pages	14
Journal	Cancer Cell
Volume	27
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2015.05.002
State	Published - Jun 8 2015

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2015.05.002

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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

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title = "CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance",

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.",

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

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year = "2015",

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doi = "10.1016/j.ccell.2015.05.002",

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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.

PY - 2015/6/8

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

Abstract

ASJC Scopus subject areas

UN SDGs

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