Abstract 2526: CP690550 inhibits interleukin-2 (IL-2), IL-9 and IL-15 mediated JAK3 activation and proliferation of T cells obtained from patients with HTLV-1-associated adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Abstract

Abstract The retrovirus, human T cell lymphotrophic virus-1 (HTLV-1) is the etiologic agent of ATL and the neurological disorder, HAM/TSP. Infection with HTLV-1 results in viral tax protein mediated constitutive activation of the JAK3/STAT5 pathway in patients' T-lymphocytes that is believed to result in malignant transformation or autoimmunity. JAK3 plays a key role in cytokine receptor-mediated signal transduction including the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 that use the common γ- chain. This suggests that inhibitors of JAK3 may be of benefit in HTLV-1-associated diseases. We evaluated the effect of a novel small molecule JAK3 inhibitor, CP690550 on the cytokine-dependent cell line, NK92. CP690550 at 50 or 100 nM effectively inhibited the proliferation of IL-2-stimulated NK92 cells, but not NK92 that were stimulated with IL-12 or the combination of IL-6 and its receptor (IL-6R) that do not utilize the common γ-chain and JAK3 for signaling and proliferation. We also demonstrated the relative specificity of this inhibitor on another cytokine-dependent cell line, 32Dβ where at 50 or 100 nM CP690550 inhibited IL-2 and JAK3 mediated proliferation but did not affect murine IL-3-mediated cell proliferation. The activation mediated phosphorylation of STAT5 in NK92 cells in response to IL-2 stimulation was inhibited by CP690550. We evaluated the action of CP690550 on the ex vivo proliferation of peripheral blood mononuclear cells (PBMC) from selected patients with the smoldering or chronic subtypes of ATL, or HAM/TSP whose PBMC are associated with the production of cytokines, in particular, IL-2, IL-9 and IL-15 that use the common γ-chain and JAK3. CP690550 at 50 nM inhibited the ex vivo spontaneous proliferation of PBMC from 11 patients with ATL and 9 patients with HAM/TSP at 6-day by means of 66% and 86.4%, respectively. CP690550 also inhibited the proliferation of NK92 cells stimulated with the 6-day ex vivo PBMC culture supernatants from ATL and HAM/TSP patients by a mean of 83.9% and 82%, respectively. We also demonstrated that CP690550 effectively inhibited the activation of the JAK3/STAT5 pathway in isolated T-cells from ATL patients. On the basis of this study, the JAK3 inhibitor CP690550 deserve further study as a potential therapeutic agent for select patients with HTLV-1-associated ATL and HAM/TSP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2526.