The DNA-helicase HELLS drives ALK- ALCL proliferation by the transcriptional control of a cytokinesis-related program
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ABSTRACT:
PROVIDER: PRJEB42006 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4993374_1.fastq.gz | Fastqsanger.gz | |||
| ERR4993374_2.fastq.gz | Fastqsanger.gz | |||
| ERR4993375_1.fastq.gz | Fastqsanger.gz | |||
| ERR4993375_2.fastq.gz | Fastqsanger.gz | |||
| ERR4993376_1.fastq.gz | Fastqsanger.gz |
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Project description:Deregulation of chromatin modifiers, including DNA helicases, are emerging as one of the mechanism underlying the transformation of anaplastic lymphoma kinase negative (ALK−) anaplastic large cell lymphoma (ALCL). We recently identified the DNA helicase HELLS as central for proficient ALK-ALCL proliferation and progression. By performing RNA-sequencing profiling coupled with bioinformatic prediction, we demonstrated that HELLS contributes to an appropriate cytokinesis via the transcriptional regulation of genes involved in cleavage furrow regulation in ALK- anaplastic large cell lymphoma
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Project description:Activating JAK and STAT mutations were discovered in many T-cell malignancies including ALK- anaplastic large cell lymphomas (ALCL). However, such mutations often occur in a minority of patients. To investigate the clinical application of targeting Janus Kinase (JAK) for ALK- ALCL, we treated ALK- cell lines of different histologic origins with JAK inhibitors. Interestingly, most exogenous cytokine independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with STAT3 phosphorylation status of tumor cells. Employing retroviral shRNA knockdown, we demonstrated that these JAK inhibitor sensitive cells were dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some but not all JAK inhibitor sensitive cells. Moreover, the mutations alone could not explain the JAK1/STAT3 dependency as wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in select JAK inhibitor sensitive cells. High levels of cytokine expression including IL-6 were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest cytokine receptor signaling was required for tumor cell survival in diverse forms of ALK- ALCL even in the presence of JAK1/STAT3 mutations. Therefore, JAK-inhibitor therapy might benefit patients with ALK- ALCL that are pSTAT3+.
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Project description:Anaplastic Large Cell Lymphoma (ALCL) is a clinical and biological heterogeneous disease including ALK positive and ALK negative systemic forms. To discover biomarkers and/or genes involved in ALK negative ALCL pathogenesis, we applied the Cancer Outlier Profile Analysis (COPA) algorithm to a gene expression profiling data set including 249 cases of T-NHLs and normal T-cells. Ectopic co-expression of ERBB4 and COL29A1 genes was detected in 24% of ALK negative ALCL patients. RNA sequencing and 5'RNA Ligase Mediated Rapid Amplification of cDNA Ends (RLM-RACE) identified two novel ERBB4 truncated transcripts, displaying intronic Transcription Starting Sites. ERBB4 expression was confirmed at protein level by western blotting and immunohistochemistry. Moreover, by luciferase assays we defined that the expression of ERBB4 aberrant transcripts is promoted by endogenous intronic Long Terminal Repeats (LTRs). In conclusion, we identified a new subclass of ALK negative ALCL characterized by aberrant expression of ERBB4 truncated transcripts carrying intronic 5'UTRs.
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Project description:Deregulation of chromatin modifiers, including DNA helicases, is emerging as one of the mechanisms underlying the transformation of anaplastic lymphoma kinase negative (ALK-) anaplastic large cell lymphoma (ALCL). We recently identified the DNA-helicase HELLS as central for proficient ALK-ALCL proliferation and progression. Here we assessed in detail its function by performing RNA-sequencing profiling coupled with bioinformatic prediction to identify HELLS targets and transcriptional cooperators. We demonstrated that HELLS, together with the transcription factor YY1, contributes to an appropriate cytokinesis via the transcriptional regulation of genes involved in cleavage furrow regulation. Binding target promoters, HELLS primes YY1 recruitment and transcriptional activation of cytoskeleton genes including the small GTPases RhoA and RhoU and their effector kinase Pak2. Single or multiple knockdowns of these genes reveal that RhoA and RhoU mediate HELLS effects on cell proliferation and cell division of ALK-ALCLs. Collectively, our work demonstrates the transcriptional role of HELLS in orchestrating a complex transcriptional program sustaining neoplastic features of ALK-ALCL.
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Project description:C/EBPβ (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPβ responsible for ALK-mediated oncogenesis. C/EBPβ was knocked down in ALK+ ALCL cell lines with a C/EBPβ-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPβ. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPβ was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPβ-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPβ in ALK-mediated oncogenesis.
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Project description:Characterization of transcriptional landscape of HELLS in T-cell lymphoma. ChIP-seq experiments against Histone Marks and RNA-Polymerase II were performed in both control and HELLS knockdown (DOX) cells. ChIP-seq against HELLS was performed in control cells.
2024-06-06 | E-MTAB-12935 | biostudies-arrayexpress
Project description:C/EBPβ (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPβ responsible for ALK-mediated oncogenesis. C/EBPβ was knocked down in ALK+ ALCL cell lines with a C/EBPβ-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPβ. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPβ was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPβ-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPβ in ALK-mediated oncogenesis. Kijk and SUDHL1 cell lines transfected with shRNA for C/EBPbeta were compared to control cells (3 biological replicates per group) and untreated cells (1 biological replicate)
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Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). Affymetrix UU133A gene expression data for a series of 32 cases of systemic Anaplastic Large Cell Lymphoma<br> (ALCL) and 5 ALCL cell lines; used to (1) confirm that tumors expressing Anaplastic Lymphoma Kinase (ALK+ ALCL) and ALK- ALCLs are different entities, (2) identify most significantly differentially expressed genes between ALK+ and ALK- samples, (3) generate a molecular signature of ALK- ALCL, (4) perform unsupervised analysis classifying ALCL in sub-groups related to morphology and clinical variables (e.g. disease stage and enrichment with 'early relapse' patients).<br> <br> Principal Investigator: Dr Georges DELSOL-- Centre de Physiopathologie Toulouse-Purpan CHU-Purpan -- Toulouse -- France -- Email: delsol.g@chu-toulouse.fr <br> Programme "Cartes d'identite des Tumeurs" (CIT) of the "Ligue Nationale Contre le Cancer" (LNCC)<br> Submitter: Fabien PETEL (petelf@ligue-cancer.net)
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