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

• Published in: Disease models & mechanisms Vol. 16; no. 10
• Main Authors: Gao, Jie, Ren, Shumei, Choonoo, Gabrielle, Chen, Guoying, Frleta, Davor, Zhong, Jun, Gupta, Namita, Sharma, Prachi, Oyejide, Adelekan, Atwal, Gurinder S., Macdonald, Lynn, Murphy, Andrew, Kuhnert, Frank
• Format: Journal Article
• Language: English
• Published: The Company of Biologists Ltd 01-10-2023; The Company of Biologists
• Subjects: ctcl; humanized mice; il-15; pdx; sezary syndrome
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.050190

ABSTRACT
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 immunodeficient 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 pathological 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 the thorough molecular understanding of the resultant PDX models to maximize their translational impact.