A STAT5B-driven mouse model of hepatosplenic γδ T cell lymphoma reveals therapeutic efficacy of JAK inhibitors

ABSTRACT: Hepatosplenic T cell lymphoma (HSTL) is a rare, aggressive disease primarily affecting young adults. The disease progresses rapidly, with patients displaying low survival rates and poor responses to standard chemotherapy-based treatments. Currently no targeted therapies are available for HSTL, and pre-clinical models to test new treatment options have not been established. Hence, new models recapitulating HSTL are needed. The JAK-STAT signalling pathway is a key pathway dysregulated in HSTL and STAT5B N642H is the most frequent oncogenic mutation. Using a transgenic mouse model, we have previously validated STAT5B N642H as a strong driver of γδ T cell lymphoma. Here, we have established clonal, murine γδ T cell lymphoma cell lines driven by oncogenic STAT5B, which resemble key features of human HSTL. The IL-2 dependent cell line, C15, displays immunophenotypic features as well as commonly dysregulated gene expression profiles shared with patient-derived HSTL cell lines. C15 cells can be engrafted intravenously into immunocompetent mice to generate an aggressive HSTL-like disease. Recipient mice display an expansion of malignant γδ T cells causing hepatosplenomegaly and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels. Using these models, we tested the potential of JAK inhibition as a targeted treatment strategy for HSTL, with the clinically-approved JAK inhibitor upadacitinib displaying significant anti-tumor efficacy against HSTL cells in vitro and in vivo. Overall, we have developed a robust, accessible and faithful preclinical model of HSTL with the advantage of immune-competence, which can facilitate the study of physiological disease mechanisms and new (immuno)therapy strategies.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE271616 | GEO | 2026/03/12

REPOSITORIES: GEO