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

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.