CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness

• DOI: 10.1038/s41375-021-01376-1
• Publication Date: 2021-08-06T11:02:51Z
• Authors: Richard Lewis; H. Carlo Maurer; Nikita Singh; Irene Gonzalez-Me...; Matthias Wirth; Markus Schick; Le Zhang; Konstandina Isaak...; Anna Katharina Sc...; Veronika Schulze; Junyan Lu; Thorsten Zenz; Katja Steiger; Roland Rad; Leticia Quintanil...; Marion Espeli; Karl Balabanian; Ulrich Keller; Stefan Habringer
• Keywords: Hyperactivation; Pathogenesis

Abstract Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with gain-of-function mutation ( C1013G ) that hyperactivates signaling, we identified as crucial activator of multiple key oncogenic pathways. hyperactivation resulted an expansion transitional B1 lymphocytes, which represent the precursors chronic lymphocytic leukemia (CLL). Indeed, led significant acceleration onset more aggressive phenotype murine Eµ-TCL1 CLL model. Hyperactivated signaling cooperated TCL1 cause distinct transcriptional program B cells, characterized by PLK1/FOXM1-associated In accordance, Eµ-TCL1;CXCR4 cells enriched signature from patients Richter’s syndrome, transformation CLL. Notably, MYC activation was associated increased expression. line this finding, additional hyperactive Eµ-Myc mouse, B-cell cancer, did not impact survival. summary, here identify co-driver phenotype.