Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

S. Sangaletti, C. Tripodo, C. Vitali, P. Portararo, C. Guarnotta, P. Casalini, B. Cappetti, S. Miotti, P. Pinciroli, F. Fuligni, F. Fais, P. P. Piccaluga (+1 others)
2013 Cancer Discovery  
Altered expression of matricellular proteins can become pathogenic in the presence of persistent perturbations in tissue homeostasis. Here, we show that autoimmunity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defective collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty
more » ... ivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5 + B cells, which underwent malignant transformation due to defective apoptosis under the pressure of neutrophil-derived trophic factors and NF-κB activation. Furthermore, this model of defective stromal remodeling during lymphomagenesis correlates with human lymphomas arising in a SPARC-defective environment, which is prototypical of CD5 + B-cell chronic lymphocytic leukemia (CLL). SIGNIFICANCE: These results reveal the importance of stromal remodeling in SLO to accommodate autoimmune lymphoproliferation while preventing lymphomagenesis. Our fi ndings reveal a link between SPARC, collagen deposition, and the engagement of the immune-inhibitory receptor LAIR-1 on neutrophils, neutrophil cell death via NETosis, and the stimulation of CD5 + B-cell proliferation. Moreover, we show that SPARC defi ciency promotes CD5 + B-cell lymphomagenesis and is correlated with CLL in humans. Cancer Discov; 4(1); 110-29. ©2013 AACR. See related commentary by Brekken, p. 25.
doi:10.1158/ pmid:24189145 fatcat:32avzwqhhrd2dppnrskmq4jxtm