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CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness

Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4(C1013G)) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic...

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Autores principales: Lewis, Richard, Maurer, H. Carlo, Singh, Nikita, Gonzalez-Menendez, Irene, Wirth, Matthias, Schick, Markus, Zhang, Le, Isaakidis, Konstandina, Scherger, Anna Katharina, Schulze, Veronika, Lu, Junyan, Zenz, Thorsten, Steiger, Katja, Rad, Roland, Quintanilla-Martinez, Leticia, Espeli, Marion, Balabanian, Karl, Keller, Ulrich, Habringer, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478649/
https://www.ncbi.nlm.nih.gov/pubmed/34363012
http://dx.doi.org/10.1038/s41375-021-01376-1
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author Lewis, Richard
Maurer, H. Carlo
Singh, Nikita
Gonzalez-Menendez, Irene
Wirth, Matthias
Schick, Markus
Zhang, Le
Isaakidis, Konstandina
Scherger, Anna Katharina
Schulze, Veronika
Lu, Junyan
Zenz, Thorsten
Steiger, Katja
Rad, Roland
Quintanilla-Martinez, Leticia
Espeli, Marion
Balabanian, Karl
Keller, Ulrich
Habringer, Stefan
author_facet Lewis, Richard
Maurer, H. Carlo
Singh, Nikita
Gonzalez-Menendez, Irene
Wirth, Matthias
Schick, Markus
Zhang, Le
Isaakidis, Konstandina
Scherger, Anna Katharina
Schulze, Veronika
Lu, Junyan
Zenz, Thorsten
Steiger, Katja
Rad, Roland
Quintanilla-Martinez, Leticia
Espeli, Marion
Balabanian, Karl
Keller, Ulrich
Habringer, Stefan
author_sort Lewis, Richard
collection PubMed
description Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4(C1013G)) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4(C1013G) B cells enriched a transcriptional signature from patients with Richter’s syndrome, an aggressive transformation of CLL. Notably, MYC activation in aggressive lymphoma was associated with increased CXCR4 expression. In line with this finding, additional hyperactive CXCR4 signaling in the Eµ-Myc mouse, a model of aggressive B-cell cancer, did not impact survival. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype.
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spelling pubmed-84786492021-10-08 CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness Lewis, Richard Maurer, H. Carlo Singh, Nikita Gonzalez-Menendez, Irene Wirth, Matthias Schick, Markus Zhang, Le Isaakidis, Konstandina Scherger, Anna Katharina Schulze, Veronika Lu, Junyan Zenz, Thorsten Steiger, Katja Rad, Roland Quintanilla-Martinez, Leticia Espeli, Marion Balabanian, Karl Keller, Ulrich Habringer, Stefan Leukemia Article Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4(C1013G)) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4(C1013G) B cells enriched a transcriptional signature from patients with Richter’s syndrome, an aggressive transformation of CLL. Notably, MYC activation in aggressive lymphoma was associated with increased CXCR4 expression. In line with this finding, additional hyperactive CXCR4 signaling in the Eµ-Myc mouse, a model of aggressive B-cell cancer, did not impact survival. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype. Nature Publishing Group UK 2021-08-06 2021 /pmc/articles/PMC8478649/ /pubmed/34363012 http://dx.doi.org/10.1038/s41375-021-01376-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lewis, Richard
Maurer, H. Carlo
Singh, Nikita
Gonzalez-Menendez, Irene
Wirth, Matthias
Schick, Markus
Zhang, Le
Isaakidis, Konstandina
Scherger, Anna Katharina
Schulze, Veronika
Lu, Junyan
Zenz, Thorsten
Steiger, Katja
Rad, Roland
Quintanilla-Martinez, Leticia
Espeli, Marion
Balabanian, Karl
Keller, Ulrich
Habringer, Stefan
CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
title CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
title_full CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
title_fullStr CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
title_full_unstemmed CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
title_short CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
title_sort cxcr4 hyperactivation cooperates with tcl1 in cll development and aggressiveness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478649/
https://www.ncbi.nlm.nih.gov/pubmed/34363012
http://dx.doi.org/10.1038/s41375-021-01376-1
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