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

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http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/15625 http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/15625 http://eprints.org/relation/isIndexCodesVersionOf http://etheses.bham.ac.uk/id/document/15625 archive 4031 disk0/00/00/28/84 2011-10-27 14:55:07 2019-01-23 09:55:02 2011-10-27 14:55:07 thesis show 0 Cader Fathima Zumla Murray Paul Vockerodt Martina Kearns Pamela University of Birmingham An investigation of the aberrant expression and activation of receptor tyrosine kinases in hodgkin’s lymphoma unpub QD QP RC RZ 10col_mede 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and dovitinib, two next generation multiple-target RTK inhibitors. 2011-07 2011-06 graduation eng author unchecked This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. public 254 University of Birmingham Institute of Cancer Studies d_ph bloodwise 2011-07 graduation