CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP.

Therapeutic Approaches

Abstract

The retrovirus, human T-cell-lymphotrophic virus-1 (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-I-encoded protein tax constitutively activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems that in turn activate the Jak3 (Janus kinase 3)/STAT5 (signal transducers and activators of transcription 5) pathway, suggesting a therapeutic strategy that involves targeting Jak3. We evaluated the action of the Jak3 inhibitor CP-690,550 on cytokine dependent ex vivo proliferation that is characteristic of peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL, or from those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15, and their receptors. CP-690,550 at 50 nM inhibited the 6-day ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by 67.1% and 86.4%, respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL T cells ex vivo. Finally, in an in vivo test of biological activity, CP-690,550 treatment of mice with a CD8 T-cell IL-15-transgenic leukemia that manifests an autocrine IL-15/IL-15Rα pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select patients with HTLV-I-associated ATL and HAM/TSP.

Authors

Ju, Wei; Zhang, Meili; Jiang, Jian-Kang; Thomas, Craig; Oh, Unsong; Bryant, Bonita R; Chen, Jing; Sato, Noriko; Tagaya, Yutaka; Morris, John C; Janik, John E; Jacobson, Steven; Waldmann, Thomas A;

Keywords

  • Adult
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation/ drug effects
  • Cytokines/ metabolism
  • Cytokines/ pharmacology
  • Enzyme Activation/ drug effects
  • Humans
  • In Vitro Techniques
  • Interleukin-15/ genetics
  • Interleukin-15/ metabolism
  • Janus Kinase 3/ antagonists & inhibitors
  • Leukemia, Experimental/ drug therapy
  • Leukemia, Experimental/ immunology
  • Leukemia, Experimental/ pathology
  • Leukemia-Lymphoma, Adult T-Cell/ drug therapy
  • Leukemia-Lymphoma, Adult T-Cell/ enzymology
  • Leukemia-Lymphoma, Adult T-Cell/ pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Paraparesis, Tropical Spastic/ drug therapy
  • Paraparesis, Tropical Spastic/ enzymology
  • Paraparesis, Tropical Spastic/ pathology
  • Phosphorylation/ drug effects
  • Piperidines
  • Pyrimidines/ pharmacology
  • Pyrroles/ pharmacology
  • STAT5 Transcription Factor/ metabolism
  • Signal Transduction/ drug effects
  • T-Lymphocytes/ drug effects
  • T-Lymphocytes/ metabolism
  • T-Lymphocytes/ pathology

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