Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B cell activation and proliferation
In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment influences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Emu-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 trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-beta-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-beta-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 LTbetaR-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. (c)2014 AACR. See related commentary by Lopez-Guerra et al., p. 1374 This article is highlighted in the In This Issue feature, p. 1355.
|Authors||Heinig, K.; Gatjen, M.; Grau, M.; Stache, V.; Anagnostopoulos, I.; Gerlach, K.; Niesner, R. A.; Cseresnyes, Z.; Hauser, A. E.; Lenz, P.; Hehlgans, T.; Brink, R.; Westermann, J.; Dorken, B.; Lipp, M.; Lenz, G.; Rehm, A.; Hopken, U. E.;|
|Publisher Name||Cancer Discovery|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12474|