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Title: Investigating the evolution of dexamethasone resistance in acute lymphoblastic leukaemia
Authors: Dormon, Katherine Louise
Issue Date: 2017
Publisher: Newcastle University
Abstract: The evolution of ALL from presentation to relapse is often accompanied by the emergence of resistance to commonly used chemotherapeutics, including dexamethasone (Dex), a synthetic glucocorticoid that has been the backbone of ALL treatment since the 1950s. In order to investigate the evolution of drug resistance we focused on the L707 cells, a matched Dex-sensitive presentation and Dex-resistant relapse pair from a patient with t(17;19) B ALL. A major genetic difference between presentation and relapse is a 5q deletion spanning 6 genes, including NR3C1, the glucocorticoid receptor and the site of action for Dex. It was found previously that the L707 presentation engrafts and proliferates faster than the relapse cells in the NSG mouse model. The loss of NR3C1 was hypothesised as the cause for reduced fitness of the relapse. This thesis investigated this, and the mechanisms behind the Dex resistance in the L707 relapse. Using shRNA approaches to look at the function of the genes in the relapse 5q deletion identified NR3C1 as the major driver of resistance but did not provide evidence that loss resulted in reduced fitness. Further in depth analysis of the L707 cells using microarrays has shown that the differences between presentation and relapse extend past the genetic differences, including alterations in transcriptional programmes. To identify further novel drivers of resistance, a whole genome in vivo CRISPR screen was carried out, implicating several genes in leukaemic fitness and Dex resistance as well as being a proof of concept for the use of these screens in primary material. Finally, an incidental finding that 697 pre B leukaemic cell line was Dex resistant in vivo, but not in vitro, and examination of these cells using RNA sequencing resulted in the finding that alterations in transcription induced by the murine microenvironment may be responsible for this change.
Description: PhD Thesis
Appears in Collections:Northern Institute for Cancer Research

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