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ABSTRACT:
PROVIDER: PRJNA1043616 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This study provides a genome-wide map of changes in degradative ubiquitination in response to proteasome inhibition in the multiple myeloma cell line MM.1S. Following proteasome inhibition with lactacystin, CUT and RUN assays were carried out to determine the genomic locations of ubiquitin in multiple myeloma cells stably expressing a flagged version of ubiquitin (MM.1S-3XFlag Ubiquitin cells). In addition, we report the DNA binding locations of the transcription factor c-MYC in basal conditions in MM.1S parental cells.
2022-11-21 | GSE193302 | GEO
Project description:Targeting of the ubiquitin-proteasome system (UPS) remains a mainstay in the treatment of multiple myeloma (MM). Hyperactivation of the closely related SUMO pathway is implicated in disease progression and associated with poor prognosis. Here we investigated the functional imbalance of aberrant SUMOylation in MM by analyzing the large CoMMpass dataset for molecular alterations associated with SUMO pathway regulation. SENP6 and SENP7, key SUMO proteases, were significantly downregulated in patients with high SUMO pathway signatures. Recurrent loss of SENP6, a negative regulator of SUMOylation, was directly linked to adverse prognosis across all disease stages. SENP6 reconstitution markedly reduced cellular growth kinetics in SENP6-deficient MM, indicating a functional role for SENP6 as a tumor suppressor. Mechanistically, SENP6 loss resulted in the accumulation of DNA damage and misfolded proteins, thereby activating the unfolded protein response, increasing reliance on proteasomal degradation, and driving synthetic lethality to therapeutic proteasome inhibition. Together, we establish SENP6 as a biologically relevant biomarker and provide a mechanistic rationale for the clinical efficacy of proteasome inhibitors in the prognostically unfavorable subgroup of SENP6-deficient MM patients.
2025-12-08 | GSE303255 | GEO
Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite significant advancements in understanding the pathogenesis and the development of novel therapeutic approaches, MM remains incurable. Emerging evidence indicates aberrant epigenetic activity at cis-regulatory elements (CREs). However, the characterization of these events and the definition of relative impact with MM phenotype is only partially known. To address this gap, we comprehensively analyzed the epigenetic changes occurring during MM progression to identify the events and the key transcriptional regulators sustaining the disease.We profiled a cohort of 55 patient MM samples at diagnosis, post-therapy, and relapse and a cohort of 16 MGUS samples using ATAC-seq. Then, we used footprinting analysis to identify detailed changes in transcription factor engagement. We conducted experiments using in vitro and in vivo methods, including primary cell line models and a MM mouse model (vk-Myc). We employed high-throughput techniques such as ChIP-seq, RNA-seq, and RNA-Single Cell. Our results were confirmed using shRNA interference, dCas9-KRAB-Mediated interference, and the usage of an independent cohort.We stratified the pervasiveness of open chromatin loci in our MM cohort. Penetrant loci were enriched for the binding of the Nuclear Respiratory Factor 1 (NRF1) in MM but not in MGUS samples. These findings were validated using 144 published ATAC-seq profiles of MM. ChIP-seq analysis on 15 MM and 6 MGUS patients confirmed that NRF1 sustains the activity of promoters and enhancers exclusively in MM but not in MGUS. A distinctive NRF1-dependent transcriptional signature of 103 genes was identified, correlating with aggressive disease and bad prognosis (CoMMpass dataset). This signature defines a group of 195 patients with a significantly poorer prognosis (20 months overall survival gap). The gene signature is enriched for survival pathways and ubiquitination. Our experiments show that NRF1 drives the proteasome homeostatic mechanism by enhancing phosphorylation and ubiquitination. NRF1 levels increase during therapy with proteasome inhibitors in our models. We identified a strong MM-specific enhancer element producing eRNA, looping towards the NRF1 gene. Interference with this eRNA downregulated NRF1 expression. Lowering eRNA in the presence of bortezomib increased cell proliferation loss, suggesting potential clinical applications for eRNA interference as an adjuvant to proteasome inhibitors.Collectively, our research supports that MM cells exhibit an addiction to NRF1, providing a survival advantage and therapy escape mechanisms. NRF1 binding reflects higher proteotoxic stress in malignant plasma cells and is crucial for their adaptability. Interfering with NRF1 and its regulatory elements significantly impairs MM therapy escape potential, highlighting its therapeutic benefit in MM treatment strategies.
2025-09-09 | GSE279761 | GEO
Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite significant advancements in understanding the pathogenesis and the development of novel therapeutic approaches, MM remains incurable. Emerging evidence indicates aberrant epigenetic activity at cis-regulatory elements (CREs). However, the characterization of these events and the definition of relative impact with MM phenotype is only partially known. To address this gap, we comprehensively analyzed the epigenetic changes occurring during MM progression to identify the events and the key transcriptional regulators sustaining the disease.We profiled a cohort of 55 patient MM samples at diagnosis, post-therapy, and relapse and a cohort of 16 MGUS samples using ATAC-seq. Then, we used footprinting analysis to identify detailed changes in transcription factor engagement. We conducted experiments using in vitro and in vivo methods, including primary cell line models and a MM mouse model (vk-Myc). We employed high-throughput techniques such as ChIP-seq, RNA-seq, and RNA-Single Cell. Our results were confirmed using shRNA interference, dCas9-KRAB-Mediated interference, and the usage of an independent cohort.We stratified the pervasiveness of open chromatin loci in our MM cohort. Penetrant loci were enriched for the binding of the Nuclear Respiratory Factor 1 (NRF1) in MM but not in MGUS samples. These findings were validated using 144 published ATAC-seq profiles of MM. ChIP-seq analysis on 15 MM and 6 MGUS patients confirmed that NRF1 sustains the activity of promoters and enhancers exclusively in MM but not in MGUS. A distinctive NRF1-dependent transcriptional signature of 103 genes was identified, correlating with aggressive disease and bad prognosis (CoMMpass dataset). This signature defines a group of 195 patients with a significantly poorer prognosis (20 months overall survival gap). The gene signature is enriched for survival pathways and ubiquitination. Our experiments show that NRF1 drives the proteasome homeostatic mechanism by enhancing phosphorylation and ubiquitination. NRF1 levels increase during therapy with proteasome inhibitors in our models. We identified a strong MM-specific enhancer element producing eRNA, looping towards the NRF1 gene. Interference with this eRNA downregulated NRF1 expression. Lowering eRNA in the presence of bortezomib increased cell proliferation loss, suggesting potential clinical applications for eRNA interference as an adjuvant to proteasome inhibitors.Collectively, our research supports that MM cells exhibit an addiction to NRF1, providing a survival advantage and therapy escape mechanisms. NRF1 binding reflects higher proteotoxic stress in malignant plasma cells and is crucial for their adaptability. Interfering with NRF1 and its regulatory elements significantly impairs MM therapy escape potential, highlighting its therapeutic benefit in MM treatment strategies.
2025-09-09 | GSE279760 | GEO
Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite significant advancements in understanding the pathogenesis and the development of novel therapeutic approaches, MM remains incurable. Emerging evidence indicates aberrant epigenetic activity at cis-regulatory elements (CREs). However, the characterization of these events and the definition of relative impact with MM phenotype is only partially known. To address this gap, we comprehensively analyzed the epigenetic changes occurring during MM progression to identify the events and the key transcriptional regulators sustaining the disease.We profiled a cohort of 55 patient MM samples at diagnosis, post-therapy, and relapse and a cohort of 16 MGUS samples using ATAC-seq. Then, we used footprinting analysis to identify detailed changes in transcription factor engagement. We conducted experiments using in vitro and in vivo methods, including primary cell line models and a MM mouse model (vk-Myc). We employed high-throughput techniques such as ChIP-seq, RNA-seq, and RNA-Single Cell. Our results were confirmed using shRNA interference, dCas9-KRAB-Mediated interference, and the usage of an independent cohort.We stratified the pervasiveness of open chromatin loci in our MM cohort. Penetrant loci were enriched for the binding of the Nuclear Respiratory Factor 1 (NRF1) in MM but not in MGUS samples. These findings were validated using 144 published ATAC-seq profiles of MM. ChIP-seq analysis on 15 MM and 6 MGUS patients confirmed that NRF1 sustains the activity of promoters and enhancers exclusively in MM but not in MGUS. A distinctive NRF1-dependent transcriptional signature of 103 genes was identified, correlating with aggressive disease and bad prognosis (CoMMpass dataset). This signature defines a group of 195 patients with a significantly poorer prognosis (20 months overall survival gap). The gene signature is enriched for survival pathways and ubiquitination. Our experiments show that NRF1 drives the proteasome homeostatic mechanism by enhancing phosphorylation and ubiquitination. NRF1 levels increase during therapy with proteasome inhibitors in our models. We identified a strong MM-specific enhancer element producing eRNA, looping towards the NRF1 gene. Interference with this eRNA downregulated NRF1 expression. Lowering eRNA in the presence of bortezomib increased cell proliferation loss, suggesting potential clinical applications for eRNA interference as an adjuvant to proteasome inhibitors.Collectively, our research supports that MM cells exhibit an addiction to NRF1, providing a survival advantage and therapy escape mechanisms. NRF1 binding reflects higher proteotoxic stress in malignant plasma cells and is crucial for their adaptability. Interfering with NRF1 and its regulatory elements significantly impairs MM therapy escape potential, highlighting its therapeutic benefit in MM treatment strategies.
2025-09-09 | GSE279764 | GEO
Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite significant advancements in understanding the pathogenesis and the development of novel therapeutic approaches, MM remains incurable. Emerging evidence indicates aberrant epigenetic activity at cis-regulatory elements (CREs). However, the characterization of these events and the definition of relative impact with MM phenotype is only partially known. To address this gap, we comprehensively analyzed the epigenetic changes occurring during MM progression to identify the events and the key transcriptional regulators sustaining the disease.We profiled a cohort of 55 patient MM samples at diagnosis, post-therapy, and relapse and a cohort of 16 MGUS samples using ATAC-seq. Then, we used footprinting analysis to identify detailed changes in transcription factor engagement. We conducted experiments using in vitro and in vivo methods, including primary cell line models and a MM mouse model (vk-Myc). We employed high-throughput techniques such as ChIP-seq, RNA-seq, and RNA-Single Cell. Our results were confirmed using shRNA interference, dCas9-KRAB-Mediated interference, and the usage of an independent cohort.We stratified the pervasiveness of open chromatin loci in our MM cohort. Penetrant loci were enriched for the binding of the Nuclear Respiratory Factor 1 (NRF1) in MM but not in MGUS samples. These findings were validated using 144 published ATAC-seq profiles of MM. ChIP-seq analysis on 15 MM and 6 MGUS patients confirmed that NRF1 sustains the activity of promoters and enhancers exclusively in MM but not in MGUS. A distinctive NRF1-dependent transcriptional signature of 103 genes was identified, correlating with aggressive disease and bad prognosis (CoMMpass dataset). This signature defines a group of 195 patients with a significantly poorer prognosis (20 months overall survival gap). The gene signature is enriched for survival pathways and ubiquitination. Our experiments show that NRF1 drives the proteasome homeostatic mechanism by enhancing phosphorylation and ubiquitination. NRF1 levels increase during therapy with proteasome inhibitors in our models. We identified a strong MM-specific enhancer element producing eRNA, looping towards the NRF1 gene. Interference with this eRNA downregulated NRF1 expression. Lowering eRNA in the presence of bortezomib increased cell proliferation loss, suggesting potential clinical applications for eRNA interference as an adjuvant to proteasome inhibitors.Collectively, our research supports that MM cells exhibit an addiction to NRF1, providing a survival advantage and therapy escape mechanisms. NRF1 binding reflects higher proteotoxic stress in malignant plasma cells and is crucial for their adaptability. Interfering with NRF1 and its regulatory elements significantly impairs MM therapy escape potential, highlighting its therapeutic benefit in MM treatment strategies.
2025-09-09 | GSE279763 | GEO
Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite significant advancements in understanding the pathogenesis and the development of novel therapeutic approaches, MM remains incurable. Emerging evidence indicates aberrant epigenetic activity at cis-regulatory elements (CREs). However, the characterization of these events and the definition of relative impact with MM phenotype is only partially known. To address this gap, we comprehensively analyzed the epigenetic changes occurring during MM progression to identify the events and the key transcriptional regulators sustaining the disease.We profiled a cohort of 55 patient MM samples at diagnosis, post-therapy, and relapse and a cohort of 16 MGUS samples using ATAC-seq. Then, we used footprinting analysis to identify detailed changes in transcription factor engagement. We conducted experiments using in vitro and in vivo methods, including primary cell line models and a MM mouse model (vk-Myc). We employed high-throughput techniques such as ChIP-seq, RNA-seq, and RNA-Single Cell. Our results were confirmed using shRNA interference, dCas9-KRAB-Mediated interference, and the usage of an independent cohort.We stratified the pervasiveness of open chromatin loci in our MM cohort. Penetrant loci were enriched for the binding of the Nuclear Respiratory Factor 1 (NRF1) in MM but not in MGUS samples. These findings were validated using 144 published ATAC-seq profiles of MM. ChIP-seq analysis on 15 MM and 6 MGUS patients confirmed that NRF1 sustains the activity of promoters and enhancers exclusively in MM but not in MGUS. A distinctive NRF1-dependent transcriptional signature of 103 genes was identified, correlating with aggressive disease and bad prognosis (CoMMpass dataset). This signature defines a group of 195 patients with a significantly poorer prognosis (20 months overall survival gap). The gene signature is enriched for survival pathways and ubiquitination. Our experiments show that NRF1 drives the proteasome homeostatic mechanism by enhancing phosphorylation and ubiquitination. NRF1 levels increase during therapy with proteasome inhibitors in our models. We identified a strong MM-specific enhancer element producing eRNA, looping towards the NRF1 gene. Interference with this eRNA downregulated NRF1 expression. Lowering eRNA in the presence of bortezomib increased cell proliferation loss, suggesting potential clinical applications for eRNA interference as an adjuvant to proteasome inhibitors.Collectively, our research supports that MM cells exhibit an addiction to NRF1, providing a survival advantage and therapy escape mechanisms. NRF1 binding reflects higher proteotoxic stress in malignant plasma cells and is crucial for their adaptability. Interfering with NRF1 and its regulatory elements significantly impairs MM therapy escape potential, highlighting its therapeutic benefit in MM treatment strategies.
2025-09-09 | GSE279762 | GEO
Project description:Relapsed/refractory multiple myeloma (r/r MM) is a disease with often poor prognosis. Hyperactive SUMO signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. Here, we found that r/r MM is characterized by a SUMO-high state, and high expression of SUMO E1 ligase (SAE1/UBA2) was associated with poor overall survival. Induced resistance to the second generation proteasome inhibitor (PI) carfilzomib (CFZ) enhanced SUMO pathway activity. Accordingly, CFZ-pretreated patients showed enhanced SUMO pathway activity in the MM compartment. Treatment of MM cell lines with subasumstat, a novel small-molecule SUMO E1 activating enzyme inhibitor, showed synergistic treatment efficacy with CFZ in both PI-sensitive and PI-resistant MM cell lines irrespective of the TP53 state. Combination therapy was effective in two murine MM xenograft models, where in vivo growth was significantly inhibited, and in patient-derived primary MM cells in vitro. Mechanistically, combined subasumstat and CFZ treatment enhanced DNA stress and apoptosis. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel potent strategy for the treatment of patients with MM.
2022-08-01 | PXD032316 | Pride
Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite significant advancements in understanding the pathogenesis and the development of novel therapeutic approaches, MM remains incurable. Emerging evidence indicates aberrant epigenetic activity at cis-regulatory elements (CREs). However, the characterization of these events and the definition of relative impact with MM phenotype is only partially known. To address this gap, we comprehensively analyzed the epigenetic changes occurring during MM progression to identify the events and the key transcriptional regulators sustaining the disease.We profiled a cohort of 55 patient MM samples at diagnosis, post-therapy, and relapse and a cohort of 16 MGUS samples using ATAC-seq. Then, we used footprinting analysis to identify detailed changes in transcription factor engagement. We conducted experiments using in vitro and in vivo methods, including primary cell line models and a MM mouse model (vk-Myc). We employed high-throughput techniques such as ChIP-seq, RNA-seq, and RNA-Single Cell. Our results were confirmed using shRNA interference, dCas9-KRAB-Mediated interference, and the usage of an independent cohort.We stratified the pervasiveness of open chromatin loci in our MM cohort. Penetrant loci were enriched for the binding of the Nuclear Respiratory Factor 1 (NRF1) in MM but not in MGUS samples. These findings were validated using 144 published ATAC-seq profiles of MM. ChIP-seq analysis on 15 MM and 6 MGUS patients confirmed that NRF1 sustains the activity of promoters and enhancers exclusively in MM but not in MGUS. A distinctive NRF1-dependent transcriptional signature of 103 genes was identified, correlating with aggressive disease and bad prognosis (CoMMpass dataset). This signature defines a group of 195 patients with a significantly poorer prognosis (20 months overall survival gap). The gene signature is enriched for survival pathways and ubiquitination. Our experiments show that NRF1 drives the proteasome homeostatic mechanism by enhancing phosphorylation and ubiquitination. NRF1 levels increase during therapy with proteasome inhibitors in our models. We identified a strong MM-specific enhancer element producing eRNA, looping towards the NRF1 gene. Interference with this eRNA downregulated NRF1 expression. Lowering eRNA in the presence of bortezomib increased cell proliferation loss, suggesting potential clinical applications for eRNA interference as an adjuvant to proteasome inhibitors.Collectively, our research supports that MM cells exhibit an addiction to NRF1, providing a survival advantage and therapy escape mechanisms. NRF1 binding reflects higher proteotoxic stress in malignant plasma cells and is crucial for their adaptability. Interfering with NRF1 and its regulatory elements significantly impairs MM therapy escape potential, highlighting its therapeutic benefit in MM treatment strategies.
2025-09-09 | GSE285195 | GEO
Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite significant advancements in understanding the pathogenesis and the development of novel therapeutic approaches, MM remains incurable. Emerging evidence indicates aberrant epigenetic activity at cis-regulatory elements (CREs). However, the characterization of these events and the definition of relative impact with MM phenotype is only partially known. To address this gap, we comprehensively analyzed the epigenetic changes occurring during MM progression to identify the events and the key transcriptional regulators sustaining the disease.We profiled a cohort of 55 patient MM samples at diagnosis, post-therapy, and relapse and a cohort of 16 MGUS samples using ATAC-seq. Then, we used footprinting analysis to identify detailed changes in transcription factor engagement. We conducted experiments using in vitro and in vivo methods, including primary cell line models and a MM mouse model (vk-Myc). We employed high-throughput techniques such as ChIP-seq, RNA-seq, and RNA-Single Cell. Our results were confirmed using shRNA interference, dCas9-KRAB-Mediated interference, and the usage of an independent cohort.We stratified the pervasiveness of open chromatin loci in our MM cohort. Penetrant loci were enriched for the binding of the Nuclear Respiratory Factor 1 (NRF1) in MM but not in MGUS samples. These findings were validated using 144 published ATAC-seq profiles of MM. ChIP-seq analysis on 15 MM and 6 MGUS patients confirmed that NRF1 sustains the activity of promoters and enhancers exclusively in MM but not in MGUS. A distinctive NRF1-dependent transcriptional signature of 103 genes was identified, correlating with aggressive disease and bad prognosis (CoMMpass dataset). This signature defines a group of 195 patients with a significantly poorer prognosis (20 months overall survival gap). The gene signature is enriched for survival pathways and ubiquitination. Our experiments show that NRF1 drives the proteasome homeostatic mechanism by enhancing phosphorylation and ubiquitination. NRF1 levels increase during therapy with proteasome inhibitors in our models. We identified a strong MM-specific enhancer element producing eRNA, looping towards the NRF1 gene. Interference with this eRNA downregulated NRF1 expression. Lowering eRNA in the presence of bortezomib increased cell proliferation loss, suggesting potential clinical applications for eRNA interference as an adjuvant to proteasome inhibitors.Collectively, our research supports that MM cells exhibit an addiction to NRF1, providing a survival advantage and therapy escape mechanisms. NRF1 binding reflects higher proteotoxic stress in malignant plasma cells and is crucial for their adaptability. Interfering with NRF1 and its regulatory elements significantly impairs MM therapy escape potential, highlighting its therapeutic benefit in MM treatment strategies.
2025-09-09 | GSE279765 | GEO