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) 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 | GSE168558 | 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
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 | GSE168552 | 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:IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia / lymphoma (ATL) and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15-/- TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra) were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma. We used microarrays to compare the gene expression profile of tumors in IL-15-/- TAX-LUC mice to IL-15+/+ TAX-LUC mice RNA was obtained from CD16/32HI and CD16/32LO cells harvested from n=2 IL-15+/+ (control)and n=2 IL-15-/- Tax tumors and was compared to look for alterations in gene expression in malignant and tumor infiltrating cells resulting from loss of IL-15 in vivo
2013-06-11 | E-GEOD-46072 | biostudies-arrayexpress
Project description:IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia / lymphoma (ATL) and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15-/- TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra) were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma. We used microarrays to compare the gene expression profile of tumors in IL-15-/- TAX-LUC mice to IL-15+/+ TAX-LUC mice
2013-06-11 | GSE46072 | GEO