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PROVIDER: PRJEB41625 | ENA |
REPOSITORIES: ENA
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Project description:Dynamic transcriptional reprogramming leads to novel immunotherapeutic vulnerabilities in myeloma
| PRJNA681554 | ENA
Project description:Multiple myeloma (MM) cells undergo metabolic reprogramming in response to a hypoxic and nutrient-deprived bone marrow microenvironment. However, it is unclear whether primary oncogenes in recurrent translocations drive metabolic heterogeneity that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase MMSET II that promotes plasma cell transformation through a global increase in H3K36me2. We identified PKCα as a novel epigenetic target that contributes to the oncogenic potential of MMSET II. RNA-sequencing of t(4;14) cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), is transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaces mitochondria-bound HK2 and reversed sensitivity towards the glycolytic blocker 3-Bromopyruvate. Additionally, we observed a metabolic shift to a less energetic state through the reduction in oxidative and glycolytic fluxes, resulting in an overall decrease in ATP production. We employed metabolomics and lactate emerged as a differential metabolite associated with PKCα. This conferred PKCα with immunomodulatory drug (IMiDs) resistance in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Altogether, we revealed novel insights into the epigenetic and metabolism crosstalk in MM and the opportunity for therapeutic intervention that leverages on the distinct metabolic program in t(4;14) myeloma.
2022-07-26 | GSE208739 | GEO
Project description:Purpose: We examined how transcriptional state changes relate to clonal selection as BRAF inhibitor resistance develops in BRAF-mutated myeloma. Methods: To this end we generated three single-cell clones from U266, a BRAFK601N -mutated myeloma cell line and DP6- a BRAFV600E myeloma cell line. All three U266 and DP6 clones were subjected to long-term dabrafenib treatment at their established IC50 doses (U266: 10uM, DP6 1nM). Bulk RNA-seq was performed before treatment, day 7, day 14, day 42 and at time of resistance. Results: Transcriptional adaptation after seven days was homogeneous for all clones, but was different across both cell lines. Oxidative phosphorylation (OxPhos) emerged as the most consistently enriched signaling pathway in persistent cells from both cell lines as compared to baseline. Conclusions: BRAF inhibition in BRAF-mutated myeloma cells leads to transcriptional reprogramming with induction of OxPhos-related genes within a brief period of time.
2022-03-13 | GSE168950 | GEO
Project description:Cancer-testis (CT) antigens are attractive targets for immunotherapeutic strategies since they are aberrantly expressed in malignant cells and not, or in limited number, in somatic tissues, except germ cells. To identify novel CT genes in multiple myeloma, we used Affymetrix HG-U133 gene expression profiles of 5 testis, 64 primary myeloma cell (MMC) and 24 normal tissue (NT) samples. A 5-filter method was developed to keep known CT genes while deleting non-CT-restricted genes. Starting from 44928 probe sets, including probe sets for 18 known CT genes, we have obtained 82 genes expressed in MMC and testis and not detected in more than 6 NT. This list includes 14 of the 18 known CT genes and 68 novel putative CT genes. Real-time RT-PCR was performed for 34 genes in 12 NT, 3 testis and 5 MMC samples and has validated the CT status of 23/34 genes (67%). We found one novel testis-restricted gene (expression in testis and tumor only) TEX14 , 8 tissue-restricted (mRNA detected in 1 or 2 non-gametogenic tissues), and 7 differentially expressed (mRNA detected in three to six non-gametogenic tissues) CT genes. Further studies are warranted to determine the immunogenicity of these novel CT antigen candidates.
2009-01-20 | E-MTAB-81 | biostudies-arrayexpress
Project description:The accessibility of cell surface proteins makes them tractable for cancer immunotherapy, but identifying suitable targets remains challenging, and resistance to treatment is common. Technical difficulties precluding the use of whole cell proteomic approaches to characterize cell surface proteins include low abundance, hydrophobicity, and a lack of protease cleavage sites. Furthermore, neither whole-cell proteomic nor transcriptomic data can accurately quantify protein expression at the plasma membrane. Resistance to immunotherapies is commonly mediated by downregulation of the target protein, a particular problem when immunotherapies fail to inhibit a specific biological pathway. Here we have used plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins and quantify for the first time the entire cell surface proteome of a primary cancer. This approach revealed a novel therapeutic target, SEMA4A, which we potently and selectively targeted with an antibody-drug conjugate in vitro and in vivo. Reduction of SEMA4A expression resulted in marked impairment of myeloma cell growth in vitro, indicating that myeloma cells cannot downregulate SEMA4A to avoid detection. Our data therefore reveal not only a novel myeloma target but provide an exemplar of a top-down approach from the unbiased characterization of a cancer cell surface proteome to novel immunotherapeutic target.
2022-01-24 | PXD014165 | Pride
Project description:In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.
2024-03-01 | GSE230466 | GEO
Project description:In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.
2024-03-01 | GSE230292 | GEO
Project description:In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.
2024-03-01 | GSE230277 | GEO
Project description:Transcriptional enhancers instruct spatiotemporal gene expression and their dysfunction has long been known as one of the primary mechanisms that drive tumorigenesis and confer malignant tumor cell behaviors. However, it is largely unknown about whether tumor cell enhancer regulation plays a role in tumor immune evasion and anti-tumor immune response. Here, we demonstrate that tumor cell deletion of Mll3 and Mll4, two members of COMPASS family for enhancer H3K4 mono-methylation, increases tumor cell immunogenicity and promotes anti-tumor immune response. Loss of Mll4 potentiates therapeutic response to anti-Pd1 blockade in the murine melanoma model. Mechanistically, Mll4 loss leads to the widespread decrease of epigenetic signatures at both typical and super-enhancers, including the super-enhancer for Ago2 subunit of RNA-induced silencing complex (RISC) and the enhancers for DNA methyltransferases Dnmt3a and Dnmt1. Downregulation of Ago2 expression leads to double-stranded RNA (dsRNAs) stress to elicit interferon response while decreased expression of Dnmt3a and Dnmt1 derepresses Gsdmd and inflammatory caspases to trigger Gsdmd-mediated pyroptosis in Mll4-deficient tumor cells. Notably, transcriptional induction of interferon signaling and Gsdmd-mediated tumor cell pyroptotic death is crucial for the increased anti-tumor immunity and the improved immunotherapeutic efficacy in Mll4-deficient tumors. These findings reveal an important immune regulatory role of tumor cell enhancer regulation and provide molecular insights into the immunotherapeutic vulnerabilities of tumors bearing MLL3/MLL4 deficiency or loss of function mutations.
2022-10-05 | GSE192714 | GEO
Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-alpha-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP-alpha and highlights the core targets of epigenetic reprogramming in t(8;21) AML. ChIP-sequencing and DNAse1-sequencing was used for the identification of a dynamic core transcriptional network in t(8;21) AML
2014-09-24 | E-GEOD-60130 | biostudies-arrayexpress