The Overexpression of Collagen Receptor DDR1 is Associated With Chromosome Instability and Aneuploidy in Diffuse Large B-Cell Lymphoma.

in Journal of cellular and molecular medicine by Sandra Margielewska-Davies, Matthew Pugh, Eszter Nagy, Ciara I Leahy, Maha Ibrahim, Eanna Fennell, Aisling Ross, Jan Bouchal, Lauren Lupino, Matthew Care, Reuben Tooze, Gary Reynolds, Zbigniew Rudzki, Wenbin Wei, William Simmons, Vikki Rand, Kelly Hunter, John J Reynolds, Grant S Stewart, Katerina Bouchalova, Iona J Douglas, Katerina Vrzalikova, Paul G Murray

TLDR

  • The study discovers a link between DDR1 and aneuploidy in Diffuse Large B-Cell Lymphoma (DLBCL) and reveals a novel mechanistic link between DDR1 signalling and chromosome instability in B cells.
  • Researchers found that DDR1 overexpression is associated with reduced expression of spindle checkpoint genes, aneuploidy, and copy number alterations in DLBCL cells.

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.

Overview

  • The study investigated the link between DDR1 (collagen receptor) and aneuploidy (chromosome instability) in Diffuse Large B-Cell Lymphoma (DLBCL).
  • The researchers found that DDR1 overexpression is associated with reduced expression of spindle checkpoint genes, aneuploidy, and copy number alterations in DLBCL cells.
  • They also discovered that collagen treatment of primary germinal centre B cells with DDR1 expression can recapitulate the aberrant transcriptional program of DLBCL and downregulate the expression of CENPE, a key mitotic spindle protein.

Comparative Analysis & Findings

  • A comparison of transcriptional signatures in DLBCL cells revealed three signatures of aneuploidy associated with DDR1 overexpression.
  • The study found that collagen treatment of primary germinal centre B cells with DDR1 expression can partially recapitulate the aberrant transcriptional program of DLBCL and downregulate CENPE expression.
  • The inhibition of CENPE and overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro.

Implications and Future Directions

  • The study reveals a novel mechanistic link between DDR1 signalling and chromosome instability in B cells, which may contribute to the development of DLBCL.
  • Future research directions include exploring the clinical significance of DDR1 expression in DLBCL and identifying potential therapeutic targets for DDR1-mediated aneuploidy.
  • The study emphasizes the importance of understanding the role of DDR1 in DLBCL and may lead to the development of new treatment strategies for this aggressive B-cell lymphoma.
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