SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity
| Autor: | Ming Wang, David R. Westhead, Matthew A. Care, Jon Laye, Gina M. Doody, Ming Du, Reuben Tooze, Andrew Jack, S. Barrans, Mario Cocco, Nicholas A. Barnes, Yuanxue Huang |
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| Rok vydání: | 2014 |
| Předmět: |
Cellular differentiation
Population Context (language use) Biology Cell Line Tumor Proto-Oncogene Proteins BATF Genetics medicine Humans Nucleotide Motifs education Regulation of gene expression B-Lymphocytes education.field_of_study Binding Sites Gene regulation Chromatin and Epigenetics Cell Differentiation medicine.disease DNA-Binding Proteins Gene Expression Regulation Neoplastic Gene expression profiling Basic-Leucine Zipper Transcription Factors Interferon Regulatory Factors Mutation Myeloid Differentiation Factor 88 Trans-Activators Cancer research Lymphoma Large B-Cell Diffuse Diffuse large B-cell lymphoma Transcription Factors IRF4 |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gku451 |
| Popis: | Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL. |
| Databáze: | OpenAIRE |
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