The overexpression of collagen receptor DDR1 is associated with chromosome instability and aneuploidy in diffuse large B-cell lymphoma
Margielewska-Davies, Sandra Pugh, Matthew Nagy, Eszter Leahy, Ciara I Ibrahim, Maha Fennell, Eanna Ross, Aisling Bouchal, Jan Lupino, Lauren Care, Matthew
Margielewska-Davies, Sandra
Pugh, Matthew
Nagy, Eszter
Leahy, Ciara I
Ibrahim, Maha
Fennell, Eanna
Ross, Aisling
Bouchal, Jan
Lupino, Lauren
Care, Matthew
Affiliation
University of Birmingham; University of Limerick; Assiut University; Palacky University; University Hospital Olomouc; University of Leeds; University Hospitals Birmingham NHS Foundation Trust; Durham University; Teesside University; Aston University; Birmingham Women's NHS Foundation Trust; Royal College of Surgeons in Ireland; University of Bahrain
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Publication date
2025-05-22
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Abstract
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.
Citation
Margielewska-Davies S, Pugh M, Nagy E, Leahy CI, Ibrahim M, Fennell E, Ross A, Bouchal J, Lupino L, Care M, Tooze R, Reynolds G, Rudzki Z, Wei W, Simmons W, Rand V, Hunter K, Reynolds JJ, Stewart GS, Bouchalova K, Douglas IJ, Vrzalikova K, Murray PG. The Overexpression of Collagen Receptor DDR1 is Associated With Chromosome Instability and Aneuploidy in Diffuse Large B-Cell Lymphoma. J Cell Mol Med. 2025 May;29(10):e70318. doi: 10.1111/jcmm.70318.
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Article