Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice.

Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth factor. Importantly, an immuno-deficient knock-in mouse model genetically engineered to express human IL-15 uniquely supported the growth of SS patient samples relative to conventional immunodeficient mouse strains. SS patient-derived xenograft (PDX) models recapacitated key pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptomic analysis revealed congruent neoplastic gene expression signatures but distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of immunodeficient humanized IL-15 mice as hosts for SS, and potentially other T and NK cell derived hematologic malignancies, PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.