Transcriptomics,Genomics

Dataset Information

24

Co-addiction to IRF4 and SPIB in ABC-DLBCL


ABSTRACT: 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. Overall design: 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), shIRF4_3'UTR (Cy5), shspiB_2_3'UTR (Cy5), shspib_2 (Cy5), chimeric repressor (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). Also in HBL-1 a shRNA targeting wild type SPIB (shspiB_2) was used in a similar time course of shRNA induction (4 arrays). Also in HBL-1 a shRNA targeting mutant SPIB (shspib_2) was used in a similar time course of shRNA induction (4 arrays). Also in HBL-1 an IRF4:SPIB chimeric repressor was used in a similar time course (4, 8, 24, 48 hrs) (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).

INSTRUMENT(S): Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)

SUBMITTER: Louis M. Staudt  

PROVIDER: GSE32456 | GEO | 2012-08-16

SECONDARY ACCESSION(S): PRJNA147741

REPOSITORIES: GEO

altmetric image

Publications


Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downreg  ...[more]

Similar Datasets

2011-07-01 | E-GEOD-22901 | ArrayExpress
| GSE22901 | GEO
| PRJNA147741 | ENA
2012-08-16 | E-GEOD-33012 | ArrayExpress
| GSE22900 | GEO
2010-12-30 | E-GEOD-22900 | ArrayExpress
2015-10-27 | E-GEOD-71526 | ArrayExpress
2013-07-22 | E-GEOD-46973 | ArrayExpress
2010-05-26 | E-GEOD-9067 | ArrayExpress
2014-08-01 | E-GEOD-58791 | ArrayExpress