CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness

• Published in: Leukemia 2021-10, Vol.35 (10), p.2895-2905
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 13/95; 38/39; 38/90; 38/91; 631/67/1990/291/1621/1915; 631/67/395; 631/67/70; 64/60; 692/420/755; 692/699/1541/1990/291/1621/1915; 82/80; Analysis; Animals; B cells; Cancer Research; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chemokine receptors; Chronic lymphocytic leukemia; Critical Care Medicine; CXCR4 protein; Disease Progression; Disease resistance; Female; Forkhead Box Protein M1 - genetics; Forkhead Box Protein M1 - metabolism; Gene Expression Regulation, Leukemic; Genetic aspects; Health aspects; Hematology; Intensive; Internal Medicine; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphatic leukemia; Lymphocytes; Lymphocytes B; Lymphoma; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myc protein; Oncology; Pathogenesis; Phenotypes; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Signal transduction; Signaling; T cell lymphoma; Transcription
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01376-1

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.