American Association for Cancer Research
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Supplementary methods, figures and legends from Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

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journal contribution
posted on 2023-04-03, 20:41 authored by Sabina Sangaletti, Claudio Tripodo, Caterina Vitali, Paola Portararo, Carla Guarnotta, Patrizia Casalini, Barbara Cappetti, Silvia Miotti, Patrizia Pinciroli, Fabio Fuligni, Franco Fais, Pier Paolo Piccaluga, Mario P. Colombo

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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 delivery 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 findings 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 deficiency 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. 25This article is highlighted in the In This Issue feature, p. 1

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