IRAK1/4 and BET bromodomain inhibitions converge on NF-κB blockade and display synergistic antitumor activity in ABC-DLBCL with MYD88L265P mutation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE159915 | GEO | 2020/10/24
REPOSITORIES: GEO
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Project description:High expression of the FOXP1 transcription factor distinguishes the highly aggressive Activated B Cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL) from the more indolent Germinal Center (GCB) DLBCL subtype and is correlated with poor prognosis. A genetic or functional role for FOXP1 in lymphomagenesis and/or tumor maintenance, however, remains unknown. Here, we report that sustained expression of FOXP1 is necessary for ABC DLBCL cell line survival. Genome-wide transcript profiling reveals that FOXP1 acts directly and indirectly by enforcing expression of known ABC DLBCL hallmarks, including the classical NF-kappaB survival pathway. Our data further suggest that FOXP1 maintains the ABC subtype distinction by repressing gene expression programs dominant in GCB DLBCL and supports a model in which the target of ABC DLBCL transformation is a transitory cell type en route from the germinal center B cell to the terminally differentiated plasma cell.
2015-12-01 | GSE64586 | GEO
Project description:IRAK1/4 and BET bromodomain inhibitions converge on NF-κB blockade and display synergistic antitumor activity in ABC-DLBCL with MYD88L265P mutation
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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:The ABC subtype of diffuse large B cell lymphoma (DLBCL) remains the least curable form of this lymphoma despite recent advances in therapy. We have combined structural and functional genomics to triangulate on new oncogenic mechanisms and devise new therapeutic strategies. RNA interference screen revealed a dependence of ABC DLBCL cell lines on MYD88 and IRAK1. High throughput resequencing of RNA (RNA-Seq) revealed frequent somatic mutations in MYD88 that preferentially occurred in the ABC DLBCL subtype. Remarkably, one third of ABC DLBCL tumor samples harbored the same amino acid substitution, L265P, in the MYD88 TIR domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in two other DLBCL subtypes, but was observed in 9% of MALT lymphomas. At a lower frequency, multiple other mutations were observed in the MYD88 TIR domain, occurring in both the ABC and GCB subtypes of DLBCL. Survival of ABC DLBCL lines bearing the L265P mutation was sustained by the mutant but not wild type MYD88 isoform, demonstrating that this MYD88 mutant is oncogenic and gain-of-function. The MYD88 L265P mutant assembled a protein complex that spontaneous triggers the phosphorylation of IRAK1, leading to NF-kB signaling, secretion of the cytokines IL-6, IL-10 and interferon-b, and JAK kinase signaling. These findings demonstrate that the MYD88 signaling pathway is integral to the pathogenesis of ABC DLBCL, providing a genetic rationale for therapeutic targeting of the MYD88 signaling pathway in this lymphoma subtype.
2010-12-30 | GSE22900 | GEO
Project description:B-cell receptor (BCR) signaling is essential for the diffuse large B-cell lymphoma (DLBCL) subtype that originates from activated B-cells (ABC). ABC-DLBCL cells are sensitive to Bruton tyrosine kinase intervention. However, ABC-DLBCL patients had overall response rates of 33-37% for Bruton tyrosine kinase inhibitors, suggesting the evaluation of combination-based treatment for improved efficacy. We investigated the efficacy and mechanism of AZD5153 combined with the Bruton tyrosine kinase inhibitor acalabrutinib in ABC-DLBCL preclinical models. AZD5153 is a bivalent BET inhibitor that simultaneously engages the two bromodomains of BRD4. Adding AZD5153 to acalabrutinib demonstrated a combination benefit in ABC-DLBCL cell lines and PDX models. Differential expression analyses in treated tumors identified significant alterations of BCR, PAX5, RELB/alternative NFκB, and toll-like receptor/interferon signaling. PAX5 is a transcription factor for BCR signaling genes and may be critical to the perpetually active BCR signaling in ABC-DLBCL. We demonstrate that AZD5153 decreases PAX5 expression, while acalabrutinib disruption to BCR signaling inhibits PAX5 activation. Furthermore, several interferons were decreased by AZD5153 and acalabrutinib in tumors. Adding IFNß1 to cells in vitro restored PAX5 activation. Our results demonstrate AZD5153 enhances the efficacy of acalabrutinib through PAX5 and BCR mechanisms that are critical for ABC-DLBCL.
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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:In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), NF-kappaB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IkappaB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-kappaB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.
2014-08-01 | GSE58791 | GEO
Project description:Small molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are in clinical trials for a variety of cancers, but patient selection strategies are limited. This is due in part to the heterogeneity of response following BET inhibition (BETi), which includes differentiation, senescence, and cell death in subsets of cancer cell lines. To elucidate the dominant features defining response to BETi, we carried out phenotypic and gene expression analysis of both treatment naïve cell lines and engineered tolerant lines. We found that both de novo and acquired tolerance to BET inhibition are driven by the robustness of the apoptotic response and that genetic or pharmacological manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further identify that ordered expression of the apoptotic genes BCL2, BCL2L1, and BAD significantly predicts response to BETi. Our findings highlight the role of the apoptotic network in response to BETi, providing a molecular basis for patient stratification and combination therapies. Gene expression profiling of A375 melanoma cells or NOMO-1 AML cells treated with DMSO or the BET inhibitor, CPI203. Also, gene expression profiling of the respective derived BETi-tolerant cells treated with DMSO or CPI203.
2016-01-07 | E-GEOD-69383 | biostudies-arrayexpress
Project description:The ABC subtype of diffuse large B cell lymphoma (DLBCL) remains the least curable form of this lymphoma despite recent advances in therapy. We have combined structural and functional genomics to triangulate on new oncogenic mechanisms and devise new therapeutic strategies. RNA interference screen revealed a dependence of ABC DLBCL cell lines on MYD88 and IRAK1. High throughput resequencing of RNA (RNA-Seq) revealed frequent somatic mutations in MYD88 that preferentially occurred in the ABC DLBCL subtype. Remarkably, one third of ABC DLBCL tumor samples harbored the same amino acid substitution, L265P, in the MYD88 TIR domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in two other DLBCL subtypes, but was observed in 9% of MALT lymphomas. At a lower frequency, multiple other mutations were observed in the MYD88 TIR domain, occurring in both the ABC and GCB subtypes of DLBCL. Survival of ABC DLBCL lines bearing the L265P mutation was sustained by the mutant but not wild type MYD88 isoform, demonstrating that this MYD88 mutant is oncogenic and gain-of-function. The MYD88 L265P mutant assembled a protein complex that spontaneous triggers the phosphorylation of IRAK1, leading to NF-kB signaling, secretion of the cytokines IL-6, IL-10 and interferon-b, and JAK kinase signaling. These findings demonstrate that the MYD88 signaling pathway is integral to the pathogenesis of ABC DLBCL, providing a genetic rationale for therapeutic targeting of the MYD88 signaling pathway in this lymphoma subtype. To generate a gene expression signature of MYD88 signaling in ABC DLBCL, the HBL-1 cell line was transduced with retroviral vectors expressing either shMYD88-4 or shMYD88-7. Following puromycin selection, shRNA expression was induced for 24 or 48 hours and gene expression was measured, comparing uninduced (Cy3) to induced (Cy5) cells, using genome-wide Agilent 4x44K oligonucleotide microarrays. A signature of NF-kB signaling in ABC DLBCL was generated by treating HBL-1 cells with the IkB kinase beta inhibitor MLN120B for 2h, 3h, 4h, 6h, 8h, 12h, 16h, and 24h (Cy5), and comparing their gene expression to untreated cells (Cy3). A signature of JAK signaling in ABC DLBCL was generated by treating HBL-1 cells with JAK inhibitor I (5 micromolar; Calbiochem) for 2h, 4h, 6h, and 8h (Cy5) and comparing their gene expression to vehicle-treated cells (DMSO, Cy3). RNA-Seq data not provided.
2010-12-30 | E-GEOD-22900 | biostudies-arrayexpress
Project description:We have developed a novel immunocompetent multi-lesion mouse model of activated B cell diffuse large B-cell lymphoma (ABC-DLBCL; the pBIC mice) that recapitulates relatively fast the molecular, cellular and tumor microenvironment of aggressive human ABC-DLBCL. We demonstrate that perturbed p53 signaling cooperates with constitutive NF-kB activation in GC-experienced plasmablasts with blocked terminal differentiation to promote lymphomagenesis and tumor progression through triggering downstream intracellular molecular addictions (e.g. deregulating Foxp1 and AID pathways) and intercellular immunosuppressive signals for evading anti-tumoral responses (e.g. MHC-II antigen presentation and deregulating PD-L1/PD-1 immune checkpoint). Our immunocompetent ABC-DLBCL murine model provides in vivo evidence that PD-1 blockade cooperates with anti-CD20-based current standard-of-care therapy to reshape the immunosuppressive TME and facilitate long-term anti-tumoral responses. Therefore, our results support that immune checkpoints may hold promising therapeutic potential in ABC-DLBCL.
2019-04-19 | GSE116288 | GEO