Oncogenetic Landscape Of Lymphomagenesis In Coeliac Disease

Abstract

Objective: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of celiac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. 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 hybridization and RNA-sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=7) 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 NFκB-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 NFκB, 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.

Small and Large Intestine (I): Malabsorption of Nutrients

“…Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of celiac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCD-II) [ 126 ]. EATL can arise de novo in patients with CeD, but up to 50% of EATL develop through an intermediary RCDII step [ 127 , 128 ].…”

STAT3gain-of-function mutations connect leukemia with autoimmune disease by pathological dysregulation of NKG2DhiCD8 killer T cells

“…In celiac disease, MICA expression is highly induced on intestinal epithelial cells by dietary gluten through IL-15. Epithelial MICA returns almost to baseline on a gluten-free diet, except in patients with refractory celiac disease type 2 who have developed clonal expansions of innate lymphocytes that often carry STAT3 GOF mutations (Meresse et al, 2004, Ettersperger et al, 2016, Cording et al, 2021, Soderquist et al, 2021, Hue et al, 2004).…”

Re: Association between intestinal neoplasms and celiac disease - beyond celiac disease and more

“…Our findings support that gene mutation is one of the factors developing malignant neoplasm in the absence of celiac disease. JAK/STAT3 signaling pathway was also reported as the main drivers of CD associated lymphomagenesis[ 3 ]. JAK/STAT pathway regulates MYC expression[ 4 ], which lead to proliferation of malignant cells.…”

“…CD is one of the significant gastrointestinal diseases and increases the risk of malignant neoplasms. In addition to CD, we believe that other underlying mechanisms contribute to the developing malignant neoplasms[ 3 ]. We believe that these facts would be a helpful to understand CD and EATL and these findings are highly pertinent and provide a context that helps understand those reported by Wang et al [ 1 ].…”