| Author |
Zhang, Meili Shinn, Paul Waldmann, Thomas A. Ju, Wei Bamford, Richard N. Maeda, Michiyuki Ferrer, Marc Petrus, Michael N. Guha, Rajarshi Thomas, Craig J. Conlon, Kevin D. O'shea, John J. Mathews Griner, Lesley A. Duveau, Damien Y. Wen, Bernard |
| Description |
Author Affiliation: Zhang M ( Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); Mathews Griner LA ( Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850); Ju W ( Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); Duveau DY ( Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850); Guha R ( Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850); Petrus MN ( Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); Wen B ( Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); Maeda M ( Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan); Shinn P ( Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850); Ferrer M ( Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850); Conlon KD ( Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); Bamford RN ( Transponics, Jacobus, PA 17347); O'Shea JJ ( Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.); Thomas CJ ( Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850); Waldmann TA ( Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892); |
| Abstract |
Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokine-dependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL. |
| Subject Keyword |
Interleukin-2 Metabolism Janus Kinases Leukemia-Lymphoma, Adult T-Cell STAT Transcription Factors Bcl-X Protein Aniline Compounds Pharmacology Animals Antineoplastic Agents Apoptosis Drug Effects Blotting, Western Cell Line, Tumor Cells, Cultured Flow Cytometry Interleukin Receptor Common Gamma Subunit Deficiency Genetics Antagonists & Inhibitors Drug Therapy Pathology Mice, Inbred NOD Mice, Knockout Mice, SCID Pyrazoles Signal Transduction Sulfonamides Xenograft Model Antitumor Assays Research Support, N.I.H., Extramural Multidisciplinary |
