Inhibition of ABL1 tyrosine kinase reduces HTLV-1 in peripheral blood mononuclear cells from HTLV-1-associated myelopathy/tropical spastic paraparesis patients
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA555427 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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 played by cellular genes in HTLV-1-infected CD4+ T cells await discovery. We combined microarray data and pathway analysis, and found that the ABL1 tyrosine kinase gene is a critical gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes. ABL1 is also part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML), and tyrosine kinase inhibitors (TKI), including imatinib, nilotinib, and dasatinib, are in safe clinical use for treating CML. To evaluate whether ABL1 is indeed critical for the pathogenesis of HAM/TSP, we investigated the effect of ABL1 inhibitors on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and DNA from 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 TKI. Treating the PBMCs with nilotinib or dasatinib produced significant reductions in the PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, a retrospective survey based on our clinical records found a rare case of HAM/TSP, where the patient 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 a significant gene for the survival of HTLV-1-infected cells and that TKI may be a potential therapeutic agent for HAM/TSP.
2020-05-26 | GSE132666 | GEO
Project description:Human T-cell leukemia virus type 1 (HTLV-1) is linked to the development of adult T-cell leukemia (ATL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and the NF-kB pathway to promote the survival of HTLV-1 infected T cells. In thsi study, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR/VEGFR2 as an essential survival factor of HTLV-1-transformed T cells. Inhibition of KDR induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4+ T cells from HAM/TSP patients. Phosphoproteomics analysis of HTLV-1 transformed cells treated with a KDR inhibitor revealed inhibition of the phosphorylation of multiple receptors/cell surface proteins, ubiquitin conjugating systems, proteases, phosphatases, apoptotic regulatory factors, adhesion/extracellular matrix proteins and viral proteins. This work suggests that HTLV-1 Tax has hijacked KDR kinase activity to promote Tax stability and the proliferation and survival of HTLV-1 infected cells.
2024-06-14 | PXD051981 | Pride
Project description:Among HTLV-1-infected individuals, the lifetime risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is associated with the HTLV-1 gene subgroup (i.e., subgroup-A or -B) in Japan. The purpose of this study is to understand the molecular mechanism responsible for this association.
2018-10-13 | GSE121201 | GEO
Project description:Among HTLV-1-infected individuals, the lifetime risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is associated with the HTLV-1 gene subgroup (i.e., subgroup-A or -B) in Japan. The purpose of this study is to understand the molecular mechanism responsible for this association.
2018-10-31 | GSE103323 | GEO
Project description:Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurodegenerative disease that affects motor, urinary, intestinal, and sensory functions. Typically, HAM/TSP is slowly progressive, but it may vary from limited motor disability after decades (very slow progression) to loss of motor function in a few years from disease onset (rapid). In this study, we aimed to identify prognostic biomarkers for HAM/TSP to support patient management. Thus, proteomic analysis of the cerebrospinal fluid (CSF) was performed with samples from HTLV-1 asymptomatic carriers (AC) (n=13) and HAM/TSP patients (n=21) with rapid, typical, and very slow progression using quantitative label-free liquid chromatography/tandem mass spectrometry. Enrichment analyses were also carried out to identify key biological processes associated with distinct neurological conditions in HTLV-1 infection. Candidate biomarkers were validated by ELISA in paired CSF and serum samples, and samples from HTLV-1-seronegative individuals (n=9) were used as controls. CSF analysis identified 602 proteins. Leukocyte/cell activation, immune response processes and neurodegeneration pathways were enriched in rapid progressors. Conversely, HTLV-1 AC and HAM/TSP patients with typical and very slow progression had enriched processes for nervous system development. Differential expression analysis showed that soluble vascular cell adhesion molecule 1 (sVCAM-1), chitotriosidase 1 (CHIT1), and cathepsin C (CTSC) were upregulated in HAM/TSP. However, only CHIT1 was significantly elevated after validation, particularly in HAM/TSP rapid progressors. In contrast, none of these biomarkers were altered in serum. Additionally, CSF CHIT1 levels in HAM/TSP patients positively correlated with the speed of HAM/TSP progression, defined as points in the IPEC-2 HAM/TSP disability scale per year of disease, and with CSF levels of phosphorylated neurofilament heavy chain, neopterin, CXCL5, CXCL10, and CXCL11. In conclusion, higher CSF levels of CHIT1 were associated with HAM/TSP rapid progression and correlated with other biomarkers of neuroinflammation and neurodegeneration. Therefore, we propose CHIT1 as a surrogate CSF biomarker to identify HAM/TSP patients with a worse prognosis.
2022-07-27 | PXD034065 | Pride
Project description:To investigate the differential expression profile of genes and microRNA (miRNA) in peripheral blood mononuclear cells (PBMCs) from patients infected with Human T-lymphotropic Virus 1 (HTLV-1), as well as their impact on progression to Tropical Spastic Paraparesis /HTLV Associated Myelopathy (PET/HAM)
2024-12-31 | GSE224047 | GEO
Project description:The goal of the study was to identify difference in gene expression between activated /CD69+ blood cells selected from HTLV-1-infected patient displaying HAM-TSP disease (HTLV-1-associated myelopathy/tropical spastic paraparesis), compared to healthy blood donor /HD (biological sample providers: Dr. Antoine Gessain, Pasteur Institute Paris and Etablissement Français du Sang)
2012-03-14 | GSE33859 | GEO
Project description:HTLV-1 preferentially infects CD4+ T cells and these cells play a central role in HTLV-1 infection. In this study, we investigated the global gene expression profile of circulating CD4+ T cells from distinct clinical status of HTLV-1-infected individuals in regard to Tax expression levels. CD4+ T cells were isolated from asymptomatic HTLV-1 carrier (HAC) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in order to identify genes involved in the HAM/TSP development. Hierarchical clustering analysis showed that healthy controls (CT) and HTLV-1-infected samples clustered separately. We also observed that HAC and HAM/TSP groups clustered separately regardless Tax expression. The gene expression profile of CD4+ T cells was compared among CT, HAC and HAM/TSP groups. The IL-27, PXN, CXCR4, GZMA, PRF1 and Foxp3 genes were differentially expressed between HAC and HAM/TSP groups and the frequency of CD4+Foxp3+ regulatory T cells (Treg) were higher in HTLV-1-infected individuals. These findings suggest that CD4+ T cells activity is distinct between HAC and HAM/TSP groups as expected. In order to study the transcriptional changes in CD4 T cell from HTLV-1-infected individuals, immunomagnetically purified CD4+ T-cells from the peripheral blood of 4 asymptomatic HTLV-1 carrier individuals (HAC) and 4 individuals with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), as well as from 4 healthy controls (CT) were isolated and processed the microarray assay according Agilent's protocol. The differential expressed genes, molecular characterization and networks analysis were evaluated using robust bioinformatic tools, then the real time PCR was done to validate the genes.
2013-06-01 | E-GEOD-38537 | biostudies-arrayexpress
Project description:The goal of the study was to identify difference in gene expression between activated /CD69+ blood cells selected from HTLV-1-infected patient displaying HAM-TSP disease (HTLV-1-associated myelopathy/tropical spastic paraparesis), compared to healthy blood donor /HD (biological sample providers: Dr. Antoine Gessain, Pasteur Institute Paris and Etablissement FranM-CM-'ais du Sang) We performed microarray gene expression profiling of Immune cells selected on the marker of early activation, CD69, by the use of MACS beads (Miltenyi Biotec), from 10.106 blood cells of two healthy blood donors and two HAM/TSP patients
2012-03-14 | E-GEOD-33859 | biostudies-arrayexpress
Project description:Individuals with Human T-Lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis are prone to pulmonary complications (e.g., bronchiectasis), linked to chronic inflammation. This study assessed the impact of HTLV-1 infection on lung inflammation by analyzing the alveolar transcriptome of A549 epithelial cells following exposure to HTLV-1. Co-culture with HTLV-1-infected MT-2 cells caused transcriptomic changes related to viral response, NF-kB activation, and inflammation. RT-qPCR confirmed elevated expression of the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2) and CSF-1 in A549 MT-2 co-cultures. Increased CSF-1 expression was mechanistically linked to NF-kB signaling, using CRISPR/Cas9 RELA knockout. Supernatant from A549 MT-2 co-cultures triggered chemotaxis and macrophage differentiation of THP-1 and primary monocytes. STRING analysis revealed enrichment in pathways associated with monocyte infiltration and bronchiectasis, aligning with clinical and multi-ancestry GWAS data. Overall, this study highlights HTLV-1's role in driving inflammation and monocyte recruitment in the alveolar epithelium, potentially contributing to viral persistence and immune evasion.
2026-06-10 | GSE312068 | GEO