title: SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity.
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.
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK Bioinformatics Group, School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Care
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Cocco
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Jon P
authors.initials: JP
authors.lastname: Laye
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barnes
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Yuanxue
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.affiliation: Haematological Malignancy Diagnostic Service, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Barrans
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Ming
authors.initials: M
authors.lastname: Du
authors.affiliation: Haematological Malignancy Diagnostic Service, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jack
authors.affiliation: Bioinformatics Group, School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Westhead
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Doody
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK Haematological Malignancy Diagnostic Service, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK r.tooze@leeds.ac.uk.
authors.forename: Reuben M
authors.initials: RM
authors.lastname: Tooze
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D059372:Nucleotide Motifs; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C099359:BATF protein, human; C076877:SPIB protein, human