SIRT3, a therapeutic target in DLBCL
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ABSTRACT:
PROVIDER: PRJNA606900 | ENA |
REPOSITORIES: ENA
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Project description:We report that in absence of ATM signaling SIRT3 stimluated pathways are critical for development of DLBCL
2020-12-09 | GSE145359 | GEO
Project description:Cancer cells frequently hijack adaptive stress response signals/pathways to protect themselves from metabolic or genetic vulnerabilities, pointing to candidate therapeutic targets. Among these SIRT3 was recently identified as a non-oncogene addiction mechanism in DLBCL through its role in glutamine metabolism. Here, we investigated downstream signaling pathways linked to SIRT3 function in lymphoma. We performed RNA-seq in DLBCL cells after SIRT3 knockdown and observed that ATF4 target genes were significantly downregulated in SIRT3 deficient cells. ATF4, a master regulator of cellular stress, was required to maintain proliferation and survival of DLBCL cells and its target genes were overexpressed in DLBCL patients as compared to normal germinal center B cells. Translation of ATF4 mRNA was inhibited in SIRT3 knockdown cells and expression of exogenous ATF4 partially rescued cell proliferation and viability inhibited by SIRT3 deficiency. Accordingly, ATF4 protein was expressed at relatively lower levels SIRT3 deficient murine lymphomas, whereas its higher expression was associated with more severe disease. We characterized mechanisms through which SIRT3 maintains ATF4 expression, downstream of its effects on glutamine entry into the TCA cycle and suppression of autophagy. Specifically, loss of SIRT3 disrupted amino acid metabolism in DLBCL cells, with subsequent impairment of ATF4 response to metabolic stressors such as glutamine depletion. Collectively, the data suggest a key SIRT3-ATF4 axis maintains survival of DLBCL cells enabling them to optimize amino acid metabolism and cope with metabolic vulnerabilities possibly associated with their high proliferative rate.
2022-09-20 | GSE158833 | GEO
Project description:Identification of FOXP1 target genes in the OCI-Ly1 DLBCL cell line by ChIP-on-chip
2013-05-03 | GSE44243 | GEO
Project description:Diffuse large B-cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B-cells. Herein, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B-cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted Class I sirtuin inhibitor, YC8-02, that phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.
2019-10-08 | GSE130751 | GEO
Project description:Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.
2016-10-12 | GSE80351 | GEO
Project description:Elucidation of FOXP1 target genes by RNA-Seq of DLBCL cell lines transfected with siRNAs targeting FOXP1 expression
2015-11-30 | E-MTAB-3740 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma and remains incurable in ~40% of patients. Coding-genome sequencing efforts identified several genes/pathways altered in this disease, including new potential therapeutic targets. However, the non-coding genome of DLBCL remains unexplored. Here we show that active superenhancers (SEs) are highly and specifically hypermutated in 99% of DLBCL samples. Such aberrant somatic hypermutation (ASHM) displays signatures of Activation Induced Deaminase activity and is linked to genes encoding B cell developmental regulators and oncogenes. To elucidate the functional consequences of SE-ASHM, we explored two recurrent mutational hotspots identified in the SEs linked to the BCL6 and BCL2 proto-oncogenes, but unmutated in normal GC B cells. These mutations prevent the binding and transcriptional downregulation by the transcriptional repressors BLIMP1 and NR3C1, respectively. Genetic correction of selected mutations restored repressor DNA binding as well as target gene transcriptional repression. Notably, this led to counter-selection of cells harboring corrected alleles, indicating oncogenic dependency from the SE mutations. This pervasive SE mutational mechanism reveals a new major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.
2022-04-26 | GSE182214 | GEO
Project description:Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with critical roles in the normal development and malignant transformation of lymphocytes. Recently we have shown that plasma cell cancers (multiple myeloma, MM) are addicted to an aberrant gene expression program ochestrated by wild-type IRF4 for their survival. Here we show that an aggressive malignancy of mature B cells, the activated B cell for of Diffuse Large B Cell lymphoma (ABC-DLBC), also depends on IRF4 for survival. With genome-wide expression profiling and localization (ChIP-Seq) assays, we identified IRF4 target genes in ABC-DLBCL as members of diverse pathways related to B cell biology and malignant behavior, distinct from IRF4 targets in MM. For example, we find the gene encoding the NFkB signal transduction adapter protein CARD11 is a target of IRF4 activation, driving the critical NFkB pathway in ABC-DLBCL. Further, we find enrichment of DNA binding motifs for ETS-IRF factors in regions of IRF4 binding in ABC-DLBCL suggesting cooperative activity between IRF4 and an ETS family transcription factor. Through complementation assays we show that IRF4 and the critical ABC-DLBCL ETS factor SPIB interact with one another and are key to ABC-DLBCL survival. Together our data show that ABC-DLBCL is addicted to the interaction between IRF4 and SPIB, in part through a positive feedback loop invovling CARD11 and the activation of the NFkB pathway. These data suggest theraepeutic potential in targeting the IRF4:SPIB interface in ABC-DLBCL.
2011-07-01 | GSE22901 | GEO
Project description:Elucidation of FOXP1 target genes in DLBCL by ChIP-Seq
| PRJEB9851 | ENA
Project description:Elucidation of FOXP1 target genes in DLBCL by RNA-Seq
| PRJEB9852 | ENA