Oncogenetic landscape of lymphomagenesis in coeliac disease.
Cording S, Lhermitte L, Malamut G, Berrabah S, Trinquand A, Guegan N, Villarese P, Kaltenbach S, Meresse B, Khater S, Dussiot M, Bras M, Cheminant M, Tesson B, Bole-Feysot C, Bruneau J, Molina TJ, Sibon D, Macintyre E, Hermine O, Cellier C, Asnafi V, Cerf-Bensussan N, Bouhnik Y, Cuenod CA, Brechignac S, Allez M, Cosnes J, Fourmestraux A, Delchier JC, Dupuis J, Haioun C, Gnaoui TE, Lerebours E, Savoye G, Tilly H, Flourie B, Coiffier B, Hebuterne X, Arab N, Filippi J, Schneider S, Zerbib F, Milpied N, Bouabdallah K, Tabrizi R, Vigouroux S, Pigneux A, Leguay T, Dilhuydy MS, Dauriac C, Bologna S, Hulin C, Bonmati C, Magnin F, Ranta D, Matysiakbudnik T, Deconinck E, Pouderoux P, Bonaz B, Gressin R, Carbonnel F, Gornet JM, Branche J, Saint-Georges G, Reimund JM, Nancey S, Nachury M, Viennot S, Zallot C, Fabiani B, Marthey L, Juvin K, Baleur YL, Kwiatek S, Saillard E, Louvel D, Roblin X, Beau P, Feugier P, Peyrin-Biroulet L, Zanaldi H, Brixi-Benmansour H, Cadiot G, Lecomte T, Bretagne JF, Casasnovas O, Caillot D, Bedenne L, Bay JO, Bouteloup C, Duclos B, Foucaud C.
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Abstract
DESIGN: Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines.
RESULTS: 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines.
CONCLUSION: Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.