Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

Abstract

In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment infl uences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell traffi cking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli. SIGNIFICANCE: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma-leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor-stroma cross-talk. Cancer Discov; 4(12); 1448-65.

The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

“…5 In this study, we asked what cellular and molecular factors determine the positioning and expansion of Cxcr5 ¡/¡ Em-Tcl cells in the MZ.…”

“…To identify additional molecules that retain Cxcr5 ¡/¡ EmTcl1 cells in the MZ, we used recently generated genome-wide expression data 5 and identified genes expressed differentially between Cxcr5 ¡/¡ Em-Tcl1 and Em-Tcl1 cells. We found upregulation of two genes encoding for lymphocyte transcription factors associated with SMZL development in Cxcr5 ¡/¡ Em-Tcl1 cells, Pax5 (log 2 fold D 0.581, p D 0.0084) and Notch2 (log 2 fold D 0.6643, p D 0.0003) (Fig.…”

“…FDCs secrete CXCL13, the ligand for the chemokine receptor CXCR5, and the CXCL13/CXCR5 signaling axis mediates the recruitment of leukemic cells toward follicular FDCs. 5 Enhanced antigen-stimulated BCR signaling has been correlated with the clinical course of human CLL. 6 In the Em-Tcl1 CLL model, we found enhanced expression of phosphorylated tyrosine kinases, i.e., ZAP-70 and BTK, indicating increased BCR activity.…”

“…Instead, Cxcr5 ¡/¡ Em-Tcl1 tumor cells resided in the splenic marginal zone (MZ). 5 The MZ is at the border between red (RP) and white pulp (WP) and serves as a transit area for haematopoietic cells coming from the bloodstream and entering the WP. Resident cells of the MZ are involved in T cell-dependent and -independent immune responses to blood-borne pathogens.…”

“…7 Despite a denied access to the follicle, we observed expansion of Cxcr5 ¡/¡ Em-Tcl1 leukemic cells within the MZ. 5 We now asked if these tumor cells have the flexibility to adapt to their microenvironment and what factors facilitate this phenotypic diversity. We found that murine and human CLL cells acquired an inducible expression of homing and adhesion factors characteristic for a follicular or MZ-like microenvironment upon niche-specific stimuli.…”