Abstract 2287: A model system to treat T-cell acute lymphoblastic leukemia with JAK inhibitors

Abstract

Abstract The IL-7 Receptor signaling pathway is necessary for the proliferation and survival of T cells. Together with collaborators, we have shown that 9% of patients with T cell acute lymphoblastic leukemia (T-ALL) have gain of function mutations in IL-7R exon 6. These mutations promote homodimerization of IL-7Rα subunits, resulting in constitutive activation of this pathway via JAK1. Approximately 20% of T-ALL patients fail to respond to conventional chemotherapy, so there is a need for additional options for these patients. We hypothesized that JAK inhibitors could be used to treat T-ALL patients, particularly those with IL-7R mutations. We established a cell line model of T-ALL driven by constitutive IL-7R signaling which grew as a leukemia in RAG1-/- mice. The model cells were established by transforming the D1 thymocyte cell line with a mutated IL-7Rα derived from a patient sequence. These cells termed D1_hIL7R_P1 are also GFP+ which allows us to monitor the proliferation of the cells in vivo. D1_hIL7R_P1 cells delivered intravenously result in an aggressive leukemia with morbidity within 18-21 days. Currently we are studying the chemotherapeutic effects of two JAK inhibitors, Ruxolitinib and Tofacitinib on T-ALL. The maximum tolerated doses for Tofacitinib and Ruxolitinib are 50 mg/kg and 150 mg/kg, respectively. Ruxolitinib appears to be the most effective, showing a reduction of leukemogenesis detected in blood and tissues after just three days of oral treatment. Additionally, we have obtained samples derived from pediatric T-ALL patients. Once growth kinetics in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice is established, we will proceed to study the efficacy of the JAK inhibitors with human leukemia cells. Citation Format: Emilee Senkevitch, Julie Hixon, Wenqing Li, Scott Durum. A model system to treat T-cell acute lymphoblastic leukemia with JAK inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2287. doi:10.1158/1538-7445.AM2015-2287