Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A new type of pathogenic transcription factor mutation targeting interferon regulatory factor 4 (IRF4) in human lymphoma

ABSTRACT: We report the characterization of a recurrent somatic mutation c.295T>C (p.C99R) in the Interferon Regulatory Factor 4 (IRF4) gene in human lymphoma in the α3-recognition helix of the IRF4 DNA-binding domain. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs). IRF4-C99R thoroughly modifies IRF4 function, blocking IRF4-dependent plasma cell induction, and specifically up-regulating lymphoma-specific genes in a degenerate Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Mus musculus

SUBMITTER: Vedran Franke

PROVIDER: E-MTAB-12522 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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. 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.

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A new type of pathogenic transcription factor mutation targeting interferon regulatory factor 4 (IRF4) in human lymphoma

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