The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing
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ABSTRACT:
PROVIDER: PRJNA849155 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19649202_1.fastq.gz | Fastqsanger.gz | |||
| SRR19649202_2.fastq.gz | Fastqsanger.gz | |||
| SRR19649203_1.fastq.gz | Fastqsanger.gz | |||
| SRR19649203_2.fastq.gz | Fastqsanger.gz | |||
| SRR19649204_1.fastq.gz | Fastqsanger.gz |
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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
Project description:Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-κB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state.
| S-EPMC9376625 | biostudies-literature
Project description:Abstract: Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 18 ATL patient samples using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared to normal lymphocytes. Several unique genes were identified that were overexpressed in leukemia cells including TNFSF11, RGS13, MAFb, CSPG2, C/EBPalpha and TCF4. 200 of the most highly overexpressed ATL genes were analyzed by the PathwayStudio 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, PCNA and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells wi BIRC5 shRNA decreased BIRC5 exprression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies. Keywords: disease state analysis
2009-02-01 | GSE14317 | GEO
Project description:To identify chromosomal alterations in ATL, SNP array analyses were performed in 19 leukemia cell samples from ATL patients and 9 ATL-related cell lines. ATL displayed complex chromosomal abnormalities, but it contained recurrent chromosomal amplification and deletion, including 14q11 and 14q32, which may be associated with the development of ATL. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved peripheral blood samples and from cell line samples.
2017-06-06 | GSE99667 | GEO
Project description:CD4-positive cells purified from peripheral blood of ATL patients. Keywords: other
2006-06-14 | GSE1466 | GEO
Project description:LMO2 regulates gene expression facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the Germinal Center (GC) reaction and is expressed in GC-derived non-Hodgkin’s lymphomas. LMO2 is one of the most powerful prognostic indicators in DLBCL patients. However, its function in GC B cells and DLBCL is currently unknown. In the present study we characterized the LMO2 transcriptome and interactome in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners such as LDB1, E2A, HEB, Lyl1, ETO2 and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, NFATc1 and LEF-1 proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF-1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provide a platform for future elucidation of LMO2 function in GC B-cells and DLBCL pathogenesis. RCK8 DLBCL cell lines were stably transfected with control plasmid or plasmid+LMO2
2012-07-12 | E-GEOD-34576 | biostudies-arrayexpress
Project description:Abstract: Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 18 ATL patient samples using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared to normal lymphocytes. Several unique genes were identified that were overexpressed in leukemia cells including TNFSF11, RGS13, MAFb, CSPG2, C/EBPalpha and TCF4. 200 of the most highly overexpressed ATL genes were analyzed by the PathwayStudio 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, PCNA and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells wi BIRC5 shRNA decreased BIRC5 exprression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies. Experiment Overall Design: Gene expression profiles of 7 control and 18 ATL patient samples were analyzed using Affymetrix HG-U133A2.0 arrays.
2009-02-08 | E-GEOD-14317 | biostudies-arrayexpress
Project description:Adult T-cell leukemia (ATL) is a fatal neoplasia derived from HTLV-1 infected T lymphocytes exhibiting constitutive activation of NF-kB. To elucidate the complex molecular mechanism of anti-tumor effect of the proteasome inhibitor, bortezomib in ATL cells, we attempted to perform gene expression profiling. Keywords: dose response
2007-10-09 | GSE6034 | GEO
Project description:HTLV-1 infected individuals stay as carriers for their lifetimes, while the rest of 5% are killed by ATL. ATL leukemogenesis is a complex process involving accumulation of multiple genetic abnormalities in HTLV-1 infected cells. To clarify genetic events underlying ATL leukemogenesis, we conducted comprehensive miRNA expression profiling in 40 ATL patients and in 22 healthy volunteers.
2012-02-23 | GSE31629 | GEO
Project description:SNP array analysis was performed using 168 ATL specimens. To obtain genotypes and intensities for each SNP, Affymetrix 250K SNP arrays were performed for 168 ATL samples.
2012-02-23 | E-GEOD-33602 | biostudies-arrayexpress