Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis
| العنوان: | Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis |
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| المؤلفون: | Kimiko Izumo, Atae Utsunomiya, Hiroshi Takashima, Toshio Matsuzaki, Ryuji Kubota, Masahisa Horiuchi, Shuji Izumo, Nobuaki Nakano, Mineki Saito, Daisuke Kodama, Masakazu Tanaka, Eiji Matsuura, Masahiro Nagai |
| المصدر: | PLoS Neglected Tropical Diseases, Vol 14, Iss 7, p e0008361 (2020) PLoS Neglected Tropical Diseases |
| بيانات النشر: | Public Library of Science (PLoS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | RNA viruses, Male, 0301 basic medicine, Cell Membranes, RC955-962, Gene Expression, Pathology and Laboratory Medicine, Biochemistry, Tyrosine Kinases, White Blood Cells, 0302 clinical medicine, Proviruses, Animal Cells, immune system diseases, hemic and lymphatic diseases, Arctic medicine. Tropical medicine, Tropical spastic paraparesis, Medicine and Health Sciences, Small interfering RNAs, Proto-Oncogene Proteins c-abl, Human T-lymphotropic virus 1, ABL, T Cells, virus diseases, Middle Aged, Viral Load, Paraparesis, Tropical Spastic, Enzymes, Nucleic acids, Dasatinib, Leukemia, Infectious Diseases, Medical Microbiology, Viral Pathogens, Viruses, Female, Cellular Structures and Organelles, Pathogens, Cellular Types, Public aspects of medicine, RA1-1270, Tyrosine kinase, Research Article, medicine.drug, Cell Binding, Adult, Cell Physiology, Immune Cells, Immunology, 030231 tropical medicine, Microbiology, Spinal Cord Diseases, 03 medical and health sciences, DNA-binding proteins, Retroviruses, Genetics, medicine, Humans, Gene Regulation, Non-coding RNA, Microbial Pathogens, Protein Kinase Inhibitors, Aged, Retrospective Studies, Blood Cells, Biology and life sciences, business.industry, Organisms, Public Health, Environmental and Occupational Health, Proteins, Membrane Proteins, Imatinib, Cell Biology, Htlv-1, medicine.disease, HTLV-I Infections, Regulatory Proteins, 030104 developmental biology, Nilotinib, DNA, Viral, Enzymology, Leukocytes, Mononuclear, Cancer research, RNA, business, Protein Kinases, Transcription Factors, Chronic myelogenous leukemia |
| الوصف: | Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP. Author summary Human T-cell leukemia virus type 1 (HTLV-1) is integrated as a provirus in the genomic DNA mainly of CD4+ T cell population in the infected people. HTLV-1-infected CD4+ T cells are transmitted via breast milk, semen, and blood transfusions. HTLV-1 is endemic in Japan, the Middle East, Africa, Caribbean islands, and Central and South America. A small proportion of infected people develop adult T-cell leukemia, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other diseases. HAM/TSP, a chronic neuroinflammatory disorder, is characterized by spastic paraparesis and urinary disturbance. HTLV-1-infected CD4+ T cells infiltrate the spinal cord and cause inflammation, which results in such neurological symptoms. We have identified the tyrosine kinase gene ABL1 as a gene frequently found in the signal transduction pathways in HTLV-1-infected CD4+ T cells. Therefore, ABL1 appears to be important in the pathogenesis of HAM/TSP. Inhibiting ABL1 with tyrosine kinase inhibitors (TKIs), which is used for chronic myelogenous leukemia (CML), reduced the proviral load (PVL) in vitro. We found a rare case of a patient with HAM/TSP and CML by our clinical records, who showed a decrease in PVL after TKI treatment for CML. Hence, TKIs are potential therapeutic agents for HAM/TSP. |
| اللغة: | English |
| تدمد: | 1935-2735 1935-2727 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::49c2e051e465c13e2f222a9cd5a7e375Test https://doaj.org/article/45b26dbcd2734f2992430d4f06be1facTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....49c2e051e465c13e2f222a9cd5a7e375 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19352735 19352727 |
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