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CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness

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Item Type:Article
Title:CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
Creators Name:Lewis, R. and Maurer, H.C. and Singh, N. and Gonzalez-Menendez, I. and Wirth, M. and Schick, M. and Zhang, L. and Isaakidis, K. and Scherger, A.K. and Schulze, V. and Lu, J. and Zenz, T. and Steiger, K. and Rad, R. and Quintanilla-Martinez, L. and Espeli, M. and Balabanian, K. and Keller, U. and Habringer, S.
Abstract: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.
Keywords:B-Cell Chronic Lymphocytic Leukemia, CXCR4 Receptors, Cell Cycle Proteins, Disease Progression, Forkhead Box Protein M1, Inbred C57BL Mice, Knockout Mice, Leukemic Gene Expression Regulation, Mutation, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Animals, Mice
Publisher:Nature Publishing Group
Page Range:2895-2905
Date:October 2021
Official Publication:https://doi.org/10.1038/s41375-021-01376-1
PubMed:View item in PubMed

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