An investigation of the aberrant expression and activation of receptor tyrosine kinases in hodgkin’s lymphoma

Cader, Fathima Zumla (2011). An investigation of the aberrant expression and activation of receptor tyrosine kinases in hodgkin’s lymphoma. University of Birmingham. Ph.D.

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Abstract

Multiple receptor tyrosine kinases (RTK) have been shown to be over-expressed in the malignant Hodgkin Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL). However, the activation status of many of these RTKs has not been studied. Furthermore, the contribution of aberrant RTK activation to the pathogenesis of HL is currently unknown. In chapter three, I have shown using a human phospho-receptor tyrosine kinase array that HL cells are characterised by the activation of multiple RTK. I have confirmed the over-expression and activation in HRS cells of two of these RTK, MET and RON and provided preliminary evidence that MET is negatively regulated by LRIG1 in these cells. In chapter four, I have shown for the first time that DDR1 is over-expressed in primary HRS cells. Furthermore, I have shown that in many cases, DDR1-expressing HRS cells are intimately associated with collagen, the ligand for DDR1. However, knockdown of DDR1 in a HL cell line in which DDR1 appeared to be constitutively phosphorylated revealed no detectable change in phenotype and few transcriptional changes. While exploring possible reasons for this, I identified that HL cells express multiple DDR1 isoforms including several novel transcripts. Finally, in chapter five, I have shown that HL cells are sensitive to the RTK inhibitor, dasatinib. Furthermore, consistent with the aberrant activation of multiple RTKs in HL cells, I observed that these cells were also sensitive to lestaurtinib and dovitinib, two next generation multiple-target RTK inhibitors.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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