Healy, Fiona
(2024)
The Role of NRAS in Acute Myeloid Leukaemia.
PhD thesis, University of Liverpool.
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Abstract
Acute Myeloid Leukaemia (AML) is a highly heterogenous blood cancer, caused by sustained proliferation of immature myeloid blast cells. Prognosis is poor, particularly in older patients, who comprise the majority of cases. Frontline chemotherapy regimens comprise cytarabine and daunorubicin, followed by stem cell transplant. However, relapse is common, and transplants are not suitable for elderly patients. Thus, it is crucial to understand and develop specific therapeutics against leukaemic drivers, to reduce toxicity and relapse potential. This includes the successful use of FLT3 inhibitors including FDA-approved Gilteritinib, and Quizartinib, currently in Phase III clinical trials. However, resistance is emerging against these inhibitors, and has previously been somewhat attributed to NRAS mutations, amongst others. Mutations within the Ras superfamily of proteins are often highly oncogenic, and NRAS mutations acting as a leukaemic driver in approximately 10% of de novo AML patients, and increases following relapse. Thus, it is crucial to understand the risk individual NRAS mutations pose, particularly following relapse, to ultimately ameliorate this risk. This thesis explores three common AML-relevant NRAS mutations, namely G12C, G12D and Q61K, and also NRAS wild-type. Using in vitro overexpression and gene editing techniques, effects of these NRAS mutants were studied at a genotypic and phenotypic level. Whilst all mutants conferred a proliferative advantage and increased leukaemogenic capacity in AML, there were differences seen in the pathways underpinning these, as well as the effects that each of these mutants have on drug sensitivity. Indeed, NRAS Q61K over-expression appeared to convey the greatest level of drug resistance. Overall, this work gives a novel perspective on the importance of NRAS mutations in AML, and identifies potential therapeutic avenues for future AML patients, as a means of improving prognosis.
| Item Type: | Thesis (PhD) |
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| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 Apr 2024 09:13 |
| Last Modified: | 16 Apr 2024 09:14 |
| DOI: | 10.17638/03179229 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3179229 |
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