Abstract 3857: Targeting HDAC1 in a novel model of cutaneous T-cell lymphoma.
Authors: Mishra Anjali , Sullivan Laura , Sams Gregory , Johns Jessica , Curphey Douglas , Falkenberg Lauren , Gibson Heather , Liu Shujun , Jaroncyk Laura , McConnell Kathleen , Wong Henry , La Perle Krista , Garzon Ramiro , Marcucci Guido , Porcu Pierluigi , Caligiuri Michael 
Published: August 2014

Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin's lymphoma composed of a spectrum of diseases of malignant clonal helper CD4+ T lymphocytes. Previous studies have shown that IL-15 acts as viability factor for CTCL cells, inhibiting apoptosis, and may work in association with other factors to maintain the malignant infiltrate in the epidermis. IL-15 is highly expressed both at mRNA and protein levels in the skin of CTCL patients. Using an IL-15 transgenic (tg) mouse model for spontaneous CTCL that clinically and pathologically mimics the human malignancy, we described a system for studying lymphomagenesis in CTCL (97th Annual Meeting of the AACR; 2010. Abstract nr. 2858). Skin lesions in these mice revealed the presence of characteristic Pautrier's microabscesses and these mice had poor survival. Cutaneous CD4+ T-cells from these mice were capable of engrafting into the skin of secondary SCID recipients, producing histological lesions of similar pathology. Consistent with human CTCL, we found that these tg mice are predominantly CD62L- (P=0.0009, N=14) with overexpression of CCR4, CLA, and CD44 (P=0.0001, N=14). Interestingly, we also observed elevated histone deacetylase-1 (Hdac1) expression in IL-15 tg mice compared to the wild type (WT) cohort (P=0.0013, N=3). We hypothesized that IL-15 regulates epigenetic changes in normal CD4+ lymphocytes by modulating Hdac1 and Hdac6. We analyzed normal human- and WT mouse- CD4+ T-cells and found that IL-15 induces upregulation of Hdac1 protein and cytoplasmic translocalization of Hdac6. To elucidate the mechanism controlling Hdac1 induction, we tested whether IL-15 stimulation leads to autoregulation of Hdac1 in vitro. Chromatin immunoprecipitation (ChIP) PCR analysis of IL-15 stimulated CD4+ T-cells revealed that Hdac1 binds to its own promoter as early as 12 hours post incubation increasing its own transcription. Similar observations were made in CD4+ T-cells from CTCL patients when compared to normal donor CD4+ T-cells suggesting that Hdac1 could be upregulated in CD4+ T-cells as a result of autoregulation from endogenous IL-15. To test Hdac-inhibitor therapy in IL-15 tg CTCL mice, we performed a randomized, placebo-controlled trial of an oral HDAC inhibitor invented at The Ohio State University, AR-42 (Arno Therapeutics Inc., Flemington, NJ). Interestingly, 100% of mice treated with AR-42 showed clinical improvement and reduced dermal lymphocytic infiltration after the treatment when compared to the placebo arm. In summary, our study provides a murine model of spontaneous CTCL that mimics the human disease, and also, demonstrate for the first time IL-15 mediated autoregulation of a histone-modifying enzyme Hdac1 in CD4+ T-cells that may contribute towards pathogenesis of CTCL. Finally, we show that AR-42 has significant efficacy in this preclinical CTCL model, which has in part paved the way for its current evaluation in a Phase I human clinical trial.

Citation Format: Anjali Mishra, Laura Sullivan, Gregory Sams, Jessica Johns, Douglas Curphey, Lauren Falkenberg, Heather Gibson, Shujun Liu, Laura Jaroncyk, Kathleen McConnell, Henry Wong, Krista La Perle, Ramiro Garzon, Guido Marcucci, Pierluigi Porcu, Michael Caligiuri. Targeting HDAC1 in a novel model of cutaneous T-cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3857. doi:10.1158/1538-7445.AM2013-3857