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Targeting the HBZ Viral Oncoprotein Transcriptional Network in Adult T-cell leukemia/lymphoma

ABSTRACT: Adult T-cell Leukemia/Lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). The transcription factor HBZ is the only virally encoded gene that is expressed in all ATLL cases, but it is unclear why it may be essential in ATLL and how it might be targeted therapeutically. Here we performed RNA interference screening of ATLL lines and discovered that their proliferation depends on the transcription factors BATF3 and IRF4, which regulate the identity of normal immune cells. These factors, which are highly expressed in ATLL, cooperatively bind and transactivate genes that distinguish ATLL from other T cell malignancies, including BATF3 itself. HBZ binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including the oncogene MYC. The BET protein inhibitor JQ1 collapsed the transcriptional network directed by HBZ and BATF3, and was consequently toxic for ATLL lines and patient samples in vitro, and blocked growth of ATLL xenografts. Our study demonstrates that the HTLV-I virus exploits a regulatory module that can potentially be attacked therapeutically with BET protein inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94409 | GEO | 2018/07/10

REPOSITORIES: GEO

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Targeting the HBZ Viral Oncoprotein Transcriptional Network in Adult T-cell leukemia/lymphoma (ChIP-Seq)

Project description:Adult T-cell Leukemia/Lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). The transcription factor HBZ is the only virally encoded gene that is expressed in all ATLL cases, but it is unclear why it may be essential in ATLL and how it might be targeted therapeutically. Here we performed RNA interference screening of ATLL lines and discovered that their proliferation depends on the transcription factors BATF3 and IRF4, which regulate the identity of normal immune cells. These factors, which are highly expressed in ATLL, cooperatively bind and transactivate genes that distinguish ATLL from other T cell malignancies, including BATF3 itself. HBZ binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including the oncogene MYC. The BET protein inhibitor JQ1 collapsed the transcriptional network directed by HBZ and BATF3, and was consequently toxic for ATLL lines and patient samples in vitro, and blocked growth of ATLL xenografts. Our study demonstrates that the HTLV-I virus exploits a regulatory module that can potentially be attacked therapeutically with BET protein inhibitors.

2018-07-10 | GSE94732 | GEO

Expression data of Jurkat cells stably expressing HBZ with or without stimulation

Project description:Human T-cell leukemia virus type 1 (HTLV-1) encodes HTLV-1 bZIP factor (HBZ), which is thought to be crucial for neoplastic and inflammatory diseases caused by HTLV-1. So, we analyzed the transcriptional profile of HBZ expressing cells and how HBZ affect the expression of apoptosis-related genes. We used microarrays to detail the effect of HTLV-1 bZIP factor (HBZ), which is encoded in the minus strand of HTLV-1 genome on gene expression. Especially how HBZ affect the expression of apoptosis-related genes. Jurkat cells stably expressing HBZ were stimulated with or without PMA and ionomycin for 9hours. Then RNA extraction and hybridization on Affymetrix microarrays were performed.

2013-06-18 | E-GEOD-48029 | biostudies-arrayexpress

Expression data of Jurkat cells stably expressing HBZ with or without stimulation

2013-06-18 | GSE48029 | GEO

The effect of HTLV-1 bZIP factor (HBZ) RNA and protein in mouse CD4 T cells

Project description:Human T-cell leukemia virus type 1 (HTLV-1) bZIP factor (HBZ) which is encoded in the minus strand of HTLV-1 provirus, possesses dual function as protein, and also as RNA. To know the effect of HBZ RNA and protein in primary T-cells, we introduced HBZ, or its mutant TTG (exclude protein activity), or SM (exclude RNA activity) with retrovirus vector into CD4 positive murine T cells, and analysed the transcriptome profiling. We found that HBZ RNA altered cell cycle progression, cell survival related genes, while HBZ protein altered immunology related genes. This microarray results demonstrated that HBZ RNA and protein possess distinct functions in primary cells. CD4 positive cells were enriched from murine splenocyte, and cultured with irradiated antigen presenting cells (APC). HBZ, or its mutant were introduced with retroviral vector. Forty eight hours after introduction, cells were washed and cultured with recombinant human IL-2. Further 48 hours after culture, virus infected cells were sorted and analysed by agilent microarray.

2016-04-01 | E-GEOD-70649 | biostudies-arrayexpress

The effect of HTLV-1 bZIP factor (HBZ) RNA and protein in mouse CD4 T cells

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The viral oncoproteins Tax and HBZ control the host mRNA splicing landscape

Project description:We demonstrate that the HTLV-1 oncoviral proteins Tax and HBZ differentially alter the transcriptome landscape in T-cells

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The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

Project description:Five percent of HTLV-1 infected subjects develops an untreatable form of cancer designated Adult T cell leukemia (ATL). The HTLV-1-encoded HBZ protein is believed to act as a viral oncogene by disarranging crucial pathways in the infected cells. Key to thisfunction is a progressive cytoplasmic-to-nuclear dislocation of HBZ and its interaction with nuclear factors whose complexity wasnot assessed until now. In this investigation we unveiled for the first time such complexity by studying the endogenous HBZinteractome in a leukemic cell line derived from an ATL patient. A high number of nuclear interactors, represented by at least 249members, were found. Among the various family of interactors, we found predominant the family involved in RNA splicing and RNAstability. A disarrangement of the splicing mechanism was demonstrated both in ATL cells and in non HTLV-1-derived leukemic cellsexpressing HBZ after genetic transfer, strongly suggesting that a major mechanism leading to HTLV-1-mediated transformationand persistence of the oncogenic state is related to this event. Our unprecedented results shed new light on the mechanisms bywhich a human retrovirus can alter the infected cell metabolism and strongly predispose and/or maintain neoplastictransformation

2022-07-27 | GSE206085 | GEO

Gene expression analysis of WT, HBZ-Tg, IFNgKO, and HBZ-Tg/IFNg KO mice.

Project description:Comprehensive analysis of gene expression in CD4+ T cells of WT, HBZ-Tg, IFNgKO, and HBZ-Tg/IFNg KO mice.

2015-08-25 | GSE69804 | GEO

Gene expression analysis of WT, HBZ-Tg, IFNgKO, and HBZ-Tg/IFNg KO mice.

Project description:Comprehensive analysis of gene expression in CD4+ T cells of WT, HBZ-Tg, IFNgKO, and HBZ-Tg/IFNg KO mice. CD4+ T cells were isolated from splenocytes of each strain. From isolated CD4+ T cells, RNAs were extracted and used for microarray analysis.

2015-08-25 | E-GEOD-69804 | biostudies-arrayexpress

Gene expression profiling in CD4+CD25+CCR4+ T-cells isolated from HAM/TSP, ATLL and healthy donor

Project description:Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. Recently, we and others have proposed that HTLV-1 preferentially infects CD4+CD25+CCR4+ T-cells. In this study, we used microarrays to examine the gene expression profiles of CD4+CD25+CCR4+ T-cells isolated from a HAM/TSP patient, an ATLL patient and a healthy donor to identify gene signatures that may be characteristic for these particular diseases.

2017-08-29 | GSE57259 | GEO

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