Genome-wide epigenetic alteration in adult T-cell leukemia cells and HTLV-1-mediated immortalized cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE71450 | GEO | 2016/05/06
SECONDARY ACCESSION(S): PRJNA291222
REPOSITORIES: GEO
Similar Datasets
Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1–associated myelopathy, and its viral transactivator Tax is central to disrupting host transcriptional control. Although individual interactions between Tax and host factors have been investigated, their global network and functional impact remain unclear. In this study, we performed proteomic analyses of Tax-associated complexes in HTLV-1–infected T-cells and mapped interactions between host factors and Tax. In addition to known nuclear factor kappa B (NF-κB) regulators, we identified the transcription factor interferon regulatory factor 4 (IRF4) as a novel interactor. Co-immunoprecipitation experiments confirmed Tax–IRF4 binding, and chromatin profiling revealed that Tax reprograms genome-wide IRF4 occupancy. In infected T-cells, IRF4 was enriched in super-enhancer (SE) regions, where Tax, IRF4, and NF-κB factors colocalized at ATL-related loci, and this was accompanied by histone acetylation changes and transcriptional activation. Functionally, Tax and IRF4 co-expression cooperatively restructured chromatin accessibility and induced aberrant gene expression programs. Moreover, ATL-associated IRF4 mutants (K59R, L70V, and S114N) partially reproduced Tax-driven chromatin remodeling and transcriptional reprogramming, suggesting that convergent mechanisms drive leukemogenesis. Collectively, these findings demonstrate that Tax exploits IRF4 to establish a novel regulatory mechanism. This interaction drives widespread epigenomic reprogramming in HTLV-1–infected T-cells. Overall, our study underscores the central role of Tax in IRF4 exploitation to induce infection-specific epigenomic changes, which offers novel insights into ATL pathogenesis and therapeutic strategies.
2026-03-31 | GSE316420 | GEO
Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1–associated myelopathy, and its viral transactivator Tax is central to disrupting host transcriptional control. Although individual interactions between Tax and host factors have been investigated, their global network and functional impact remain unclear. In this study, we performed proteomic analyses of Tax-associated complexes in HTLV-1–infected T-cells and mapped interactions between host factors and Tax. In addition to known nuclear factor kappa B (NF-κB) regulators, we identified the transcription factor interferon regulatory factor 4 (IRF4) as a novel interactor. Co-immunoprecipitation experiments confirmed Tax–IRF4 binding, and chromatin profiling revealed that Tax reprograms genome-wide IRF4 occupancy. In infected T-cells, IRF4 was enriched in super-enhancer (SE) regions, where Tax, IRF4, and NF-κB factors colocalized at ATL-related loci, and this was accompanied by histone acetylation changes and transcriptional activation. Functionally, Tax and IRF4 co-expression cooperatively restructured chromatin accessibility and induced aberrant gene expression programs. Moreover, ATL-associated IRF4 mutants (K59R, L70V, and S114N) partially reproduced Tax-driven chromatin remodeling and transcriptional reprogramming, suggesting that convergent mechanisms drive leukemogenesis. Collectively, these findings demonstrate that Tax exploits IRF4 to establish a novel regulatory mechanism. This interaction drives widespread epigenomic reprogramming in HTLV-1–infected T-cells. Overall, our study underscores the central role of Tax in IRF4 exploitation to induce infection-specific epigenomic changes, which offers novel insights into ATL pathogenesis and therapeutic strategies.
2026-03-31 | GSE316418 | GEO
Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1–associated myelopathy, and its viral transactivator Tax is central to disrupting host transcriptional control. Although individual interactions between Tax and host factors have been investigated, their global network and functional impact remain unclear. In this study, we performed proteomic analyses of Tax-associated complexes in HTLV-1–infected T-cells and mapped interactions between host factors and Tax. In addition to known nuclear factor kappa B (NF-κB) regulators, we identified the transcription factor interferon regulatory factor 4 (IRF4) as a novel interactor. Co-immunoprecipitation experiments confirmed Tax–IRF4 binding, and chromatin profiling revealed that Tax reprograms genome-wide IRF4 occupancy. In infected T-cells, IRF4 was enriched in super-enhancer (SE) regions, where Tax, IRF4, and NF-κB factors colocalized at ATL-related loci, and this was accompanied by histone acetylation changes and transcriptional activation. Functionally, Tax and IRF4 co-expression cooperatively restructured chromatin accessibility and induced aberrant gene expression programs. Moreover, ATL-associated IRF4 mutants (K59R, L70V, and S114N) partially reproduced Tax-driven chromatin remodeling and transcriptional reprogramming, suggesting that convergent mechanisms drive leukemogenesis. Collectively, these findings demonstrate that Tax exploits IRF4 to establish a novel regulatory mechanism. This interaction drives widespread epigenomic reprogramming in HTLV-1–infected T-cells. Overall, our study underscores the central role of Tax in IRF4 exploitation to induce infection-specific epigenomic changes, which offers novel insights into ATL pathogenesis and therapeutic strategies.
2026-03-31 | GSE316417 | GEO
Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1–associated myelopathy, and its viral transactivator Tax is central to disrupting host transcriptional control. Although individual interactions between Tax and host factors have been investigated, their global network and functional impact remain unclear. In this study, we performed proteomic analyses of Tax-associated complexes in HTLV-1–infected T-cells and mapped interactions between host factors and Tax. In addition to known nuclear factor kappa B (NF-κB) regulators, we identified the transcription factor interferon regulatory factor 4 (IRF4) as a novel interactor. Co-immunoprecipitation experiments confirmed Tax–IRF4 binding, and chromatin profiling revealed that Tax reprograms genome-wide IRF4 occupancy. In infected T-cells, IRF4 was enriched in super-enhancer (SE) regions, where Tax, IRF4, and NF-κB factors colocalized at ATL-related loci, and this was accompanied by histone acetylation changes and transcriptional activation. Functionally, Tax and IRF4 co-expression cooperatively restructured chromatin accessibility and induced aberrant gene expression programs. Moreover, ATL-associated IRF4 mutants (K59R, L70V, and S114N) partially reproduced Tax-driven chromatin remodeling and transcriptional reprogramming, suggesting that convergent mechanisms drive leukemogenesis. Collectively, these findings demonstrate that Tax exploits IRF4 to establish a novel regulatory mechanism. This interaction drives widespread epigenomic reprogramming in HTLV-1–infected T-cells. Overall, our study underscores the central role of Tax in IRF4 exploitation to induce infection-specific epigenomic changes, which offers novel insights into ATL pathogenesis and therapeutic strategies.
2026-03-31 | GSE316419 | 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:Initially, ATL cell lines (MT-1 or KK-1) were stably transfected with reporter plasmid for HTLV-1 Tax expression, and single clones were isolated . This reporter in composed of Tax responsive element upstream of d2EGFP fluorescent protein. d2EGFP is expressed upon Tax expression in any individual cell. To compare transcriptomes of Tax(-) and Tax(+) cells, FACS sorting was done for d2EGFP(-) and d2EGFP(+) populations and RNA sequencing was performed.
2018-02-02 | GSE108601 | GEO
Project description:Adult T-cell leukaemia-lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1). ATL cells constitutively activate anti-apoptotic signals through nuclear factor kappaB (NF-κB)-mediated gene expression. The molecular chaperon heat shock protein 90 (HSP90) plays a crucial role on NF-κB-mediated anti-apoptotic activity in ATL cells and HSP90 inhibitors, such as 17-DMAG and NVP-AUY922, have demonstrated their anti-ATL activities. A novel class of orally active inhibitors of cytosolic HSP90α and β, pimitespib, demonstrated its highly selective anti-ATL cell effects both ex-vivo and in vivo preclinical models. Ten ATL-related cell lines achieved their IC50 below 0.5µM dose of TAS-116 while CD4 lymphocytes derived from healthy donors were less harmed than ATL cells. TAS-116 efficiently induces Tax-degradation and IκB-α accumulation to Tax-positive cell-lines. DNA microarray profiling followed by a variety of pathway analysis revealed that TAS-116 down-regulated NF-κB activating pathways in Tax-positive cells and cell cycle promoting pathways in Tax-negative cells and induces anti-ATL effect. Oral administration of TAS-116 to ATL-cell xenograft model mice also demonstrated the growth inhibitory effects against tumor cells. Consequently, TAS-116, one of the most evolved HSP90 inhibitor, may become a promising option against ATL therapy.
2022-02-18 | GSE168554 | GEO
Project description:Adult T-cell leukaemia-lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1). ATL cells constitutively activate anti-apoptotic signals through nuclear factor kappaB (NF-κB)-mediated gene expression. The molecular chaperon heat shock protein 90 (HSP90) plays a crucial role on NF-κB-mediated anti-apoptotic activity in ATL cells and HSP90 inhibitors, such as 17-DMAG and NVP-AUY922, have demonstrated their anti-ATL activities. A novel class of orally active inhibitors of cytosolic HSP90α and β, pimitespib, demonstrated its highly selective anti-ATL cell effects both ex-vivo and in vivo preclinical models. Ten ATL-related cell lines achieved their IC50 below 0.5µM dose of TAS-116 while CD4 lymphocytes derived from healthy donors were less harmed than ATL cells. TAS-116 efficiently induces Tax-degradation and IκB-α accumulation to Tax-positive cell-lines. DNA microarray profiling followed by a variety of pathway analysis revealed that TAS-116 down-regulated NF-κB activating pathways in Tax-positive cells and cell cycle promoting pathways in Tax-negative cells and induces anti-ATL effect. Oral administration of TAS-116 to ATL-cell xenograft model mice also demonstrated the growth inhibitory effects against tumor cells. Consequently, TAS-116, one of the most evolved HSP90 inhibitor, may become a promising option against ATL therapy.
2022-02-18 | GSE168557 | GEO
Project description:Adult T-cell leukaemia-lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1). ATL cells constitutively activate anti-apoptotic signals through nuclear factor kappaB (NF-κB)-mediated gene expression. The molecular chaperon heat shock protein 90 (HSP90) plays a crucial role on NF-κB-mediated anti-apoptotic activity in ATL cells and HSP90 inhibitors, such as 17-DMAG and NVP-AUY922, have demonstrated their anti-ATL activities. A novel class of orally active inhibitors of cytosolic HSP90α and β, pimitespib, demonstrated its highly selective anti-ATL cell effects both ex-vivo and in vivo preclinical models. Ten ATL-related cell lines achieved their IC50 below 0.5µM dose of TAS-116 while CD4 lymphocytes derived from healthy donors were less harmed than ATL cells. TAS-116 efficiently induces Tax-degradation and IκB-α accumulation to Tax-positive cell-lines. DNA microarray profiling followed by a variety of pathway analysis revealed that TAS-116 down-regulated NF-κB activating pathways in Tax-positive cells and cell cycle promoting pathways in Tax-negative cells and induces anti-ATL effect. Oral administration of TAS-116 to ATL-cell xenograft model mice also demonstrated the growth inhibitory effects against tumor cells. Consequently, TAS-116, one of the most evolved HSP90 inhibitor, may become a promising option against ATL therapy.
2022-02-18 | GSE168556 | GEO
Project description:Adult T-cell leukaemia-lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1). ATL cells constitutively activate anti-apoptotic signals through nuclear factor kappaB (NF-κB)-mediated gene expression. The molecular chaperon heat shock protein 90 (HSP90) plays a crucial role on NF-κB-mediated anti-apoptotic activity in ATL cells and HSP90 inhibitors, such as 17-DMAG and NVP-AUY922, have demonstrated their anti-ATL activities. A novel class of orally active inhibitors of cytosolic HSP90α and β, pimitespib, demonstrated its highly selective anti-ATL cell effects both ex-vivo and in vivo preclinical models. Ten ATL-related cell lines achieved their IC50 below 0.5µM dose of TAS-116 while CD4 lymphocytes derived from healthy donors were less harmed than ATL cells. TAS-116 efficiently induces Tax-degradation and IκB-α accumulation to Tax-positive cell-lines. DNA microarray profiling followed by a variety of pathway analysis revealed that TAS-116 down-regulated NF-κB activating pathways in Tax-positive cells and cell cycle promoting pathways in Tax-negative cells and induces anti-ATL effect. Oral administration of TAS-116 to ATL-cell xenograft model mice also demonstrated the growth inhibitory effects against tumor cells. Consequently, TAS-116, one of the most evolved HSP90 inhibitor, may become a promising option against ATL therapy.
2022-02-18 | GSE168555 | GEO