The chemistry technology section at NCGC has aided the Waldmann lab (NCI) in using a Jak3 inhibitor for the potential treatment of ATL and HAM/TSP. 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 IL-2, IL-9 and IL-15 autocrine/paracrine systems, that in turn, activate the Jak3/STAT5 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 with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve 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 means of 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-15Ra 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.
National Cancer Institute
Tom Waldmann, Ph.D.
Public Health Impact
This study offers insight into new therapeutic options for adult T cell leukemia (ATL) and the neurological disorder, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
Ju W, Zhang M, Jiang JK, et al. CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP. Blood, 2011;117(6):1938-1946.
The JAK inhibitor Tofacitinib shows preclinical promise as a therapy for ATL and HAM/TSP.