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Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B cell activation and proliferation

Authors

  • K. Heinig
  • M. Gätjen
  • M. Grau
  • V. Stache
  • I. Anagnostopoulos
  • K. Gerlach
  • R.A. Niesner
  • Z. Cseresnyes
  • A.E. Hauser
  • P. Lenz
  • T. Hehlgans
  • R. Brink
  • J. Westermann
  • B. Dörken
  • M. Lipp
  • G. Lenz
  • A. Rehm
  • U.E. Höpken

Journal

  • Cancer Discovery

Citation

  • Canc Discov 4: 1448-1465

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 (FDCs) 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 LTβR-dependent stroma–leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor–stroma cross-talk.


DOI

doi:10.1158/2159-8290.CD-14-0096