The contribution of discoidin domain receptor 1 to the pathogenesis of diffuse large B cell lymphoma

Margielewska, Sandra Karolina (2018). The contribution of discoidin domain receptor 1 to the pathogenesis of diffuse large B cell lymphoma. University of Birmingham. Ph.D.

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Abstract

Collagen is the ligand for the discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase that is over-expressed in Hodgkin lymphoma. However, the role of DDR1 in diffuse large B cell lymphoma (DLBCL) is not known. I showed that DDR1 is over-expressed in a subset of DLBCL where it positively correlates with expression of its collagen ligands, and negatively correlates with expression of mitotic spindle genes. DDR1 correlated genes also overlapped with three aneuploidy signatures and DDR1 expression correlated significantly with autosomal aneuploidy index. RNAseq analysis revealed that over-expression of DDR1 in primary germinal centre B cells down-regulated expression of CENPE, an essential component of the mitotic spindle checkpoint that when inactivated leads to chromosome mis-segregation and aneuploidy. CENPE expression was also significantly reduced in primary DLBCL. Moreover, I showed that the constitutive activation of DDR1 in an in vitro lymphoma model led to aneuploidy. Finally, I showed that DDR1 can be inhibited by three small molecules and established the basis for in vivo model to test these inhibitors in DLBCL xenograft. My data provide evidence that DDR1 can induce aneuploidy in B cells, and as such identify a mechanism to potentially explain the link between chronic inflammation and lymphomagenesis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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