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Heinig, Kristina; Gätjen, Marcel; Grau, Michael; Stache, Vanessa; Anagnostopoulos, Ioannis; Gerlach, Kerstin; Niesner, Raluca A.; Cseresnyes, Zoltan; Hauser, Anja E.; Lenz, Peter; Hehlgans, Thomas; Brink, Robert; Westermann, Jörg; Dörken, Bernd; Lipp, Martin; Lenz, Georg; Rehm, Armin; Höpken, Uta E.

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

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  • Media type: E-Article
  • Title: Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation
  • Contributor: Heinig, Kristina; Gätjen, Marcel; Grau, Michael; Stache, Vanessa; Anagnostopoulos, Ioannis; Gerlach, Kerstin; Niesner, Raluca A.; Cseresnyes, Zoltan; Hauser, Anja E.; Lenz, Peter; Hehlgans, Thomas; Brink, Robert; Westermann, Jörg; Dörken, Bernd; Lipp, Martin; Lenz, Georg; Rehm, Armin; Höpken, Uta E.
  • imprint: American Association for Cancer Research (AACR), 2014
  • Published in: Cancer Discovery
  • Language: English
  • DOI: 10.1158/2159-8290.cd-14-0096
  • ISSN: 2159-8274; 2159-8290
  • Keywords: Oncology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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.</jats:p><jats:p>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.</jats:p><jats:p>See related commentary by López-Guerra et al., p. 1374</jats:p><jats:p>This article is highlighted in the In This Issue feature, p. 1355</jats:p>
  • Access State: Open Access