Although chronic inflammation is implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis-segregation. CENPE expression was also downregulated following DDR1 activation in two B-cell lymphoma lines and was lost in most DDR1-expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.

Department of Clinical and Molecular Pathology Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Olomouc Czech Republic

Department of Histopathology Birmingham Heartlands Hospital University Hospitals Birmingham NHS Foundation Trust UK

Department of Pediatrics Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Olomouc Czech Republic

Experimental Haematology Leeds Institute of Cancer and Pathology University of Leeds Leeds UK

Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK

Institute of Immunology and Immunotherapy University of Birmingham Birmingham UK

Limerick Digital Cancer Research Centre Bernal Institute and Health Research Institute and School of Medicine University of Limerick Limerick Ireland

National Horizons Centre Teesside University Darlington UK

Royal College of Surgeons in Ireland Medical University of Bahrain Manama Bahrain

School of Biosciences Aston University Birmingham UK

School of Health and Life Sciences Teesside University Middlesbrough UK

South Egypt Cancer Institute Assiut University Assiut Egypt

The Palatine Centre Durham University Durham UK

West Midlands Regional Genetics Laboratory Birmingham Women's NHS Foundation Trust Birmingham UK

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