Abstract:
UNLABELLED: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.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Heinig K,Gätjen M,Grau M,Stache V,Anagnostopoulos I,Gerlach K,Niesner RA,Cseresnyes Z,Hauser AE,Lenz P,Hehlgans T,Brink R,Westermann J,Dörken B,Lipp M,Lenz G,Rehm A,Höpken UEdoi
10.1158/2159-8290.CD-14-0096subject
Has Abstractpub_date
2014-12-01 00:00:00pages
1448-65issue
12eissn
2159-8274issn
2159-8290pii
2159-8290.CD-14-0096journal_volume
4pub_type
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