Abstract 2858: A novel mouse model for cutaneous T-cell lymphoma reveals a role for IL-15 and activity of a new oral HDAC inhibitor

Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin9s lymphoma representing a spectrum of diseases composed of malignant clonal CD4 (+) helper T lymphocytes. The etiology of CTCL remains to be elucidated and no animal models for CTCL are known. We quantified expression of IL-15 in patients with CTCL and demonstrated aberrant overexpression of IL-15 compared to normal CD4+ T cells (Fold increase = 7.476 ± 1.788 N=3, P=0.0073), that showed direct correlation with the stage of the disease (Fold increase in IL-15 in Stage I patients vs. Stage III patients = 3.283 ± 0.8246 vs. 7.476 ± 1.788, N=3 each, P=0.02). We engineered a transgenic (tg) mouse to constitutively and globally overexpress murine IL-15. These mice develop alopecia and cutaneous lesions in all mice within 6 weeks of birth, characterized by erythematous plaques/patches, erythroderma, pruritis and early death compared to wild type (WT) controls (49 weeks vs. 100 weeks, P=0.0003). Skin lesions showed an infiltration of atypical lymphocyte in the dermis and throughout the epidermis including the formation of classic Pautrier9s microabscesses as seen in human CTCL. Immunophenotypic analysis of the skin T-cells from these mice revealed ∼25 fold increase in CD3+ T-cells compared to WT littermates. Intradermal CD4+ cells from CTCL mice were predominantly CD62L- and significantly higher than WT mice (P=0.007). Immunohistochemistry showed high expression of cutaneous lymphocyte antigen (CLA) and CCR4 on skin sections of CTCL mice, consistent with a skin-specific homing pattern as seen in human CTCL. Cells obtained from the skin of these IL-15tg CTCL mice could be successfully engrafted into skin of SCID recipient mice with reproducible histological lesions. Consistent with human studies, CTCL mice exhibited significantly increased levels of Hdac-1 in CD4+ T cells when compared to their WT counterparts (P = 0.0013). To investigate the importance of IL-15 in this process, we cultured sorted mouse WT (CD3+CD4+) T-cells in medium supplemented with 100ng/ml IL-15 and observed a significant increase in Hdac-1 expression at the mRNA and protein level within 10 days of culture, compared to freshly isolated WT CD4+ T cells (N=3 each, p =0.02). In a randomized, placebo-controlled trial of an orally administered novel HDAC inhibitor, AR-42 (Arno Therapeutics, Inc, Parsippany, NJ; Sargeant AM et al, Cancer Research, 2008) to IL-15 tg mice with CTCL, we observed an improvement in skin lesions and a marked reduction in T-cell dermal infiltrate as early as 12 days post-treatment. In conclusion, we provide evidence for a reproducible in vivo mouse model of spontaneous CTCL that appears to mimic the human condition. Further, we provide evidence for a role of aberrant IL-15 expression in the genesis of both human and experimental CTCL, and alterations in Hdac-1 expression that may to serve as an appropriate target for a novel oral HDAC inhibitor now in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2858. doi:10.1158/1538-7445.AM2011-2858