Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.757708
Title: Pathophysiology and treatment of myelodysplasia with del(5q)
Author: Bello, Erica
ISNI:       0000 0004 7430 5173
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Abstract:
The myelodysplastic syndrome (MDS) with deletion of chromosome 5q [del(5q)] is a distinct subtype of MDS characterised by refractory hypoplastic anaemia and the del(5q) as the sole karyotypic abnormality. There is a clinical need for novel treatments for MDS with del(5q). A more complete understanding of the pathophysiology of del(5q) MDS would likely impact on development of new therapies and improve patients outcome. The aim of this D.Phil. project was to investigate various aspects of the pathophysiology of MDS with del(5q) and potential therapeutic approaches for this MDS subtype. Mutations of the CSNK1A1 gene, which maps to the commonly deleted region on chromosome 5q, were found to be rare events in a large cohort of del(5q) MDS patients. Moreover, del(5q) MDS patients with CSNK1A1 mutation showed significant up-regulation of genes involved in the Wnt/Î2-catenin pathway. These data support the notion that CSNK1A1 is an important gene in the pathogenesis of MDS with del(5q). The mechanism of L-leucine-mediated enhancement of erythropoiesis in the MDS with del(5q) was also investigated. L-leucine was found to increase proliferation and differentiation of cultured erythroblasts from MDS del(5q) patients through the activation of the mTOR pathway and increased translation of mTOR-regulated 5'Terminal Oligo Pyrimidine tract (TOP) mRNAs. Lastly, in a proof-of-principle study, the CRISPR/Cas9 system was used to correct a TP53 mutation in the chronic myeloid leukaemia cell line K562. Correction of the TP53 mutation by homology-directed repair (HDR) was obtained but corrected K562 cells also harboured additional genetic changes in the TP53 locus. This study provided new insights into the pathogenesis of MDS with del(5q), and into the mode of action of the translation enhancer L-leucine in this disorder.
Supervisor: Pellagatti, Andrea ; Boultwood, Jacqueline Sponsor: Bloodwise
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.757708  DOI: Not available
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