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

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-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE60925 | GEO | 2014/09/01

SECONDARY ACCESSION(S): PRJNA259830

REPOSITORIES: GEO

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Project description:Lymphotoxin-mediated activation of the lymphotoxin-Î² receptor (LTÎ²R) has been implicated in several physiological and pathological processes, including lymphoid organ development, T-cell maturation, and solid and hematopoietic malignancies. Its role in T-cell acute lymphoblastic leukemia (T-ALL) or other T-cell malignancies has remained however to be investigated. Here we show that the genes encoding lymphotoxin (LT)-Î± and LTÎ² were expressed in T-ALL patient samples, more abundantly in the TAL/LMO molecular subtype, and in the TEL-JAK2 mouse model of cortical/mature T-ALL. Surface LTÎ±1Î²2 protein was detected in primary mouse T-ALL cells, but only upon phorbol ester stimulation or absence of microenvironmental LTÎ²R interaction. Indeed, in contrast to leukemic cells collected from transplanted Ltbrâ/â mice or from co-cultures with Ltbrâ/â mouse embryonic fibroblasts (MEF), those collected from Ltbr+/+ mice or from Ltbr+/+ MEF co-cultures presented no surface LT expression. Supporting the notion that LT signaling plays a role in T-ALL, inactivation of the Ltbr gene in mice resulted in a statistically significant delay in TEL-JAK2-induced leukemia onset. Expression of the Lta and Ltb genes was found to be increased at the early asymtptomatic stages of TEL-JAK2 T-ALL, when only low proportions of malignant thymocytes are present in normal sized thymus. Interestingly, young asymptomatic TEL-JAK2;Ltbrâ/â mice presented significantly less leukemic thymocytes than TEL-JAK2;Ltbr+/+ mice. Together, these data indicate that early lymphotoxin expression by T-ALL cells activates LTÎ²R signaling in thymic stromal cells, thus promoting leukemogenesis. Primary T-ALL samples were obtained at diagnosis from bone marrow and/or peripheral blood with high leukemia involvement (>85%), and enriched by density centrifugation over Ficoll-Paque (GE Healthcare). Microarray analysis were performed on samples from patients with newly diagnosed T-ALL accrued from 2000 to 2013 at Centro Infantil Boldrini, Campinas, Brazil. Thymic samples, obtained from children undergoing cardiac surgery, were gently minced in culture medium and subsequently subjected to density centrifugation.

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

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