Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA127949 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:RNA interference screens identified the transcription factor IRF4 as essential for the survival of the activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Analysis of IRF4 genomic targets in ABC-DLBCL and Multiple Myeloma (MM) revealed that IRF4 regulates distinct networks in these cancers. IRF4 peaks in ABC-DLBCL, but not MM, were enriched for a composite ETS-IRF DNA motif that can be bound by heterodimers of IRF4 and the ETS-family transcription factor SPIB, whose expression is also essential for ABC-DLBCL survival. Gene expression and ChIP-Seq analysis identified essential genes co-regulated by IRF4 and SPIB. Together, these factors regulate a critical oncogenic loop by activating CARD11, which controls ABC-DLBCL survival via the NF-kB pathway. The interaction between IRF4 and SPIB presents an attractive therapeutic target in this aggressive lymphoma.
2012-08-16 | GSE32456 | 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. Gene expression was analyzed using Agilent human 4X44K oligo gene expression arrays. Cell lines (HBL1, OCILY3, TMD8-ABC-DLBCL; KMS12-MM) were infected with control (shControl, Cy3) or shIRF4_3'UTR (Cy5) constructs, and changes in gene expression were monitored over time after induction of the shRNA with doxycyclin. For each of the three ABC-DLBCL cell line a four timepoint series (24, 48, 72, 96 hrs) of shRNA induction was analyzed, for a total of 12 arrays. In HBL-1 a second shRNA targeting the IRF4 cds (shIRF4_cds) was used in a similar time course of shRNA induction (4 arrays). For the KMS12 MM cell line a three point time course was analyzed using the shIRF4_3'UTR with one technical (using the same RNA sample) duplicate time point measurement (4 arrays). ChIP-Seq data not provided.
2011-07-01 | E-GEOD-22901 | biostudies-arrayexpress
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:JAK kinases classically signal by activating STAT transcription factors, but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B cell lymphomas (DLBCL), JAK signaling is a feature of the ABC subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. While STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88 and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials.
2017-02-08 | GSE86265 | GEO
Project description:JAK kinases classically signal by activating STAT transcription factors, but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B cell lymphomas (DLBCL), JAK signaling is a feature of the ABC subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. While STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88 and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials.
2017-02-08 | GSE86264 | GEO
Project description:Knowledge of essential oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells bearing an oncogenic mutation while sparing normal cells. Lenalidomide is emerging as an active agent in diffuse large B cell lymphoma (DLBCL), especially for the activated B cell-like (ABC) subtype, but the mechanism of its action is unknown. Here we show that lenalidomide kills ABC DLBCL cells by augmenting the production of interferon 3/4, which these cells are predisposed to produce by their oncogenic MYD88 mutations. Lenalidomide stimulates the type I interferon pathway by suppressing IRF4, a repressor of IRF7. IRF4 is required for ABC DLBCL viability and is both a target and an amplifier of NF-kB signaling in this lymphoma subtype. Blockade of B cell receptor (BCR) signaling synergized with lenalidomide to reduce IRF4 levels, increase interferon 3/4 secretion, decrease NF-kB, and kill ABC DLBCL cells, suggesting therapeutic combinations that exploit the oncogenic signaling pathways in this cancer.
2012-08-16 | GSE33012 | GEO
Project description:Knowledge of essential oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells bearing an oncogenic mutation while sparing normal cells. Lenalidomide is emerging as an active agent in diffuse large B cell lymphoma (DLBCL), especially for the activated B cell-like (ABC) subtype, but the mechanism of its action is unknown. Here we show that lenalidomide kills ABC DLBCL cells by augmenting the production of interferon 3/4, which these cells are predisposed to produce by their oncogenic MYD88 mutations. Lenalidomide stimulates the type I interferon pathway by suppressing IRF4, a repressor of IRF7. IRF4 is required for ABC DLBCL viability and is both a target and an amplifier of NF-kB signaling in this lymphoma subtype. Blockade of B cell receptor (BCR) signaling synergized with lenalidomide to reduce IRF4 levels, increase interferon 3/4 secretion, decrease NF-kB, and kill ABC DLBCL cells, suggesting therapeutic combinations that exploit the oncogenic signaling pathways in this cancer. For the OCILY10 cell line treated with 10 uM lenalidamide, a four point time course of 3, 6, 24, and 48 hours was analyzed (n=4). For the TMD8 cell line treated with 10 uM lenalidamide, a four point time course of 3, 6, 24, and 48 hours was analyzed (n=4).
2012-08-16 | E-GEOD-33012 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-B and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-B activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-B activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-B and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-B in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.
2023-04-22 | PXD036363 | Pride
Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-kB and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-kB activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-kB activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-kB and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-kB in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.
2023-04-24 | PXD038951 | Pride
Project description:Constitutive activation of the nuclear factor-kappa B (NF-kB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the IkB-like protein NFKBIZ that binds NF-kB subunits and enhances transactivation of some NF-kB target genes while repressing others, to be upregulated in ACB compared to GCB DLBCL primary patient samples (p=5.1 x 10^-37). Knockdown of NFKBIZ by RNA interference was toxic to ABC but not GCB DLBCL cell lines. Gene expression profiling following NFKBIZ knockdown significantly downregulated a large number of NF-kB target genes, suggesting a central role in regulating NF-kB signaling. To further investigate the molecular mechanisms of how NFKBIZ mediates NF-kB signaling in ABC DLBCL, we performed immunoprecipitations and detected an interaction of NFKBIZ with both p50 and p52 NF-kB subunits, indicating that both the canonical and non-canonical NF-kB pathways are regulated by NFKBIZ. Collectively, our data imply that NFKBIZ is required for NF-kB signaling in ABC DLBCL and thus might represent a promising molecular target for future therapies. The complete dataset is comprised of three experiments with the male HBL-1 ABC DLBCL cell line: a) 8 paired GEP measurements after NFKBIZ inhibition by shRNA, b) 6 paired GEP measurements after applying the MLN inhibitor and c) 4 two-color measurements after applying a MALT inhibitor. This dataset includes 4 two-color measurements of the male HBL-1 ABC DLBCL cell line after applying a MALT inhibitor.
2013-07-22 | E-GEOD-46973 | biostudies-arrayexpress