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• W2949240113 abstract "Follicular lymphoma (FL) is usually an indolent lymphoma with a median survival of 10 to 15 years. However, ~15% of patients have a very poor outcome because their FL transformed to a more aggressive diffuse large B cell lymphoma (DLBCL) or developed early resistance to front-line chemotherapy. Identifying these patients with high-risk FL represents a currently unmet clinical need. Recent sequencing efforts have identified recurrent genetic events that contribute to the pathogenesis of FL, but their clinical significance remain unknown. We first identified a FAS mutation in a patient with primary-refractory FL and subsequently found FAS mutations to be associated with an increased risk of histological transformation and a tendency to develop therapeutic resistance. FAS, a key death receptor in the extrinsic apoptotic pathway, plays a fundamental role in immune homeostasis by initiating apoptosis in lymphocytes once activated by FAS ligand (FASL) from neighboring cells. We confirmed that the most common FAS mutation, (Y232*), inhibited FAS-mediated apoptosis in lymphoma cell lines, but did not induce therapeutic resistance in vitro. We hypothesized that FAS mutations would increase tumor growth and cause therapeutic resistance in vivo, due to critical interactions with FASL within the tumor microenvironment that were not present in our in vitro model. Using a mouse model of lymphoma, we assessed the effect of mutant FAS on lymphoma growth and chemosensitivity, and observed that a single Fas mutation significantly accelerated lymphoma growth and led to inferior response to chemotherapy in comparison to the Fas wild type lymphoma. However, the Fas mutant phenotype was no longer significant when the same cells were injected in immunosuppressed mice, suggesting that FAS-FASL interactions between tumor cells and the microenvironment are important in controlling lymphoma growth. Finally, to gain more insight into the biology of human FAS-mutant lymphomas, we compared the gene expression profiles of FAS-mutant versus FAS-wild-type lymphomas that were obtained from patients with relapsed refractory DLBCL, and found that FAS-mutant lymphomas have a potential regulatory B cell phenotype, that may allow them to overcome anti-tumor immune mechanisms and confer these cancer cells with an advantage for survival. A better understanding of the involvement of FAS mutations and their interactions with the microenvironment could lead to identification of novel therapeutic targets from which patient could benefit. %%%%Le lymphome folliculaire (FL) est un lymphome indolent qui presente une survie moyenne de 10 a 15 ans. Par contre, environ 15% des patients atteint de FL voit leur situation s'aggraver, soit par l'evolution de la maladie en une forme plus agressive, a savoir le lymphome diffus a grandes cellules B (DLBCL), ou encore en developpant une resistance a la chimiotherapie de premiere ligne. Pouvoir identifier ces patients a haut risque permettrait de mieux les traiter. Des efforts de sequencage des cellules cancereuses de ces…" @default.
• W2949240113 created "2019-06-27" @default.
• W2949240113 creator A5054384912 @default.
• W2949240113 date "2016-01-01" @default.
• W2949240113 modified "2023-09-28" @default.
• W2949240113 title "The role of FAS in lymphoma" @default.
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