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21598290cd140096-sup-126301_2_supp_0_nbqthc.mov (1.01 MB)

Supplementary Movie 1 from Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

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posted on 2023-04-03, 20:43 authored by Kristina Heinig, Marcel Gätjen, Michael Grau, Vanessa Stache, Ioannis Anagnostopoulos, Kerstin Gerlach, Raluca A. Niesner, Zoltan Cseresnyes, Anja E. Hauser, Peter Lenz, Thomas Hehlgans, Robert Brink, Jörg Westermann, Bernd Dörken, Martin Lipp, Georg Lenz, Armin Rehm, Uta E. Höpken

Supplementary Movie S1. Follicular motility of Emu-Tcl1 leukemia cells. The Movie complements Figure 4J.

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ARTICLE ABSTRACT

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 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 trafficking 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. ©2014 AACR.See related commentary by López-Guerra et al., p. 1374This article is highlighted in the In This Issue feature, p. 1355