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 (CXCR4C1013G) 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;CXCR4C1013G 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.
Highlights
CXCR4 is a G-protein-coupled receptor regulating hematopoietic stem cell homeostasis, myelopoiesis, lymphopoiesis, and homing of immune cells toward its ligand C-X-C motif chemokine 12 (CXCL12) [1,2,3]
In this study we co-expressed CXCR4C1013G with the B-cell oncogenes T-cell lymphoma/leukemia 1 (TCL1) and MYC to investigate the effects of enhanced CXCR4 signaling on B-cell leukemogenesis and lymphomagenesis
Hyperactivated CXCR4 functioned as an oncogene cooperating with TCL1 to accelerate chronic lymphocytic leukemia (CLL) progression and development of aggressive B-cell lymphoma
Summary
CXCR4 is a G-protein-coupled receptor regulating hematopoietic stem cell homeostasis, myelopoiesis, lymphopoiesis, and homing of immune cells toward its ligand C-X-C motif chemokine 12 (CXCL12) [1,2,3]. CXCR4 is phosphorylated at the C-terminus and rapidly internalized after binding of CXCL12 [5]. B cells in particular are highly dependent on the interaction of CXCR4 and its ligand CXCL12 at multiple stages during the germinal center reaction [10]. CXCR4 is of particular interest in chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), having been associated with adverse prognosis in both diseases [14, 15]. CXCR4 is overexpressed in CLL patients and involved in interactions of CLL cells with their microenvironment, the protection from apoptosis by the provided ligand CXCL12 [16,17,18]. In DLBCL, CXCR4 expression correlates with bone marrow infiltration [19] and has been implied in mediating resistance to B-cell receptor and PI3K inhibitors [20]
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