SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity

Research output: Contribution to journalArticlepeer-review

Authors

  • Matthew A Care
  • Mario Cocco
  • Jon P Laye
  • Yuanxue Huang
  • Ming Wang
  • Sharon Barrans
  • Ming Du
  • Andrew Jack
  • David R Westhead
  • Gina M Doody
  • Reuben M Tooze

Colleges, School and Institutes

External organisations

  • University of Leeds
  • University of Cambridge
  • Leeds Teaching Hospitals NHS Trust

Abstract

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.

Details

Original languageEnglish
Pages (from-to)7591-7610
Number of pages20
JournalNucleic Acids Research
Volume42
Issue number12
Publication statusPublished - Jul 2014

Keywords

  • B-Lymphocytes/cytology, Basic-Leucine Zipper Transcription Factors/metabolism, Binding Sites, Cell Differentiation, Cell Line, Tumor, DNA-Binding Proteins/metabolism, Gene Expression Regulation, Neoplastic, Humans, Interferon Regulatory Factors/metabolism, Lymphoma, Large B-Cell, Diffuse/genetics, Mutation, Myeloid Differentiation Factor 88/genetics, Nucleotide Motifs, Proto-Oncogene Proteins/metabolism, Trans-Activators/metabolism, Transcription Factors/metabolism