Similar Datasets
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks driven by IRF4. To discover unique molecular vulnerabilities in MM centered on IRF4, we employ a multi-omics approach integrating functional genomics screening, spatial proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, therefore defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease have markers of SWI/SNF activity, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path to effectively treat this incurable disease.
2024-01-11 | MSV000093842 | MassIVE
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
2024-05-01 | GSE253706 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
2024-05-01 | GSE253703 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
2024-05-01 | GSE253713 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
2024-05-01 | GSE253712 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
2024-05-01 | GSE253711 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
2024-05-01 | GSE253708 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.
2024-05-01 | GSE253707 | GEO
Project description:The transcription factor IRF4 (interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses. Current therapies for myeloma can extend survival but are not curative. Hence, new therapeutic strategies are needed that target molecular pathways shared by all subtypes of myeloma. Here we show, using a loss-of-function, RNA-interference-based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genome-wide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells.
| S-EPMC2542904 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-12-21 | E-GEOD-53542 | biostudies-arrayexpress