Abstract Low grade intestinal T-cell lymphoma (LGITL) is the most common gastrointestinal cancer in cats and is hypothesized to arise from chronic inflammation (lymphoplasmacytic enteritis, LPE), paralleling human refractory celiac disease II (RCD II). RCD II is now classified as an indolent neoplasm characterized by clonal T-cell expansion and JAK/STAT pathway mutations. Fifty percent of RCD II cases will progress to enteropathy-associated T-cell lymphoma, an aggressive disease with a five-year survival of 3-20% with treatment. We propose that feline LPE-LGITL is a naturally occurring translational model for the progression of intestinal inflammation to T-cell neoplasia. To investigate parallels between the human and feline conditions, we performed bulk RNA sequencing on 141 intestinal biopsies (duodenum and ileum) from 71 cats across the LPE-LGITL spectrum. Gene set enrichment analysis revealed that the top upregulated pathways in LGITL included T-cell activation and differentiation, with an enrichment for alpha-beta T-cell and NKT-like/cytotoxic signatures. These findings suggest the tumor cell of origin is an activated, intraepithelial alpha-beta T-cell with NK-like features, similar to the proposed cell of origin in human RCD II. We also identified the activating STAT5BN642H mutation in feline LGITL, and a subset of LPE cases, supporting a stepwise progression from inflammation to neoplasia. Finally, T-cell receptor analysis of LGITL shows multiple unique expanded T-cell clones in a single sample. This suggests LGITL is a cancer with neoplastic cell diversity/heterogeneity, an unusual phenotype that has also been observed in RCD II. Although feline LPE is not driven by gluten, given the similarities in transcriptomic, genetic, and pathological features, we propose that cats offer a valuable preclinical model to study the pathogenesis and treatment of intestinal intraepithelial T-cell lymphomas. Citation Format: Shay Curry, Emily Rout, Adam Harris, Cora Contreras, Robert Burnett, Kelly Hughes, Paula Schaffer, Lauren Harris, Craig Webb, Anne Avery. A naturally occurring feline model for human indolent intestinal T-cell neoplasia abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr A022.
Curry et al. (Wed,) studied this question.