PhD Study : The role of cooperating mutations in acute myeloid leukaemia

Summary

Background:

Acute myeloid leukaemia (AML) is a progressive malignancy that arises from impaired differentiation of hematopoietic progenitor cells. While many AML patients respond to induction therapy, relapse and refractory disease is common (1). Recent whole genome sequencing efforts have defined the driver landscape in AML and provided novel classifications and disease stratification (2).

While studying mutational events in single genes is essential in cancer biology, accumulating evidence suggests that the clinical effect of driver mutations is modified by the wider genomic context in which they occur. Indeed, in a study of >1,500 AML patients, two or more driver mutations were identified in 86% of cases and the outcome of patients harbouring some of the most frequently mutated genes in AML, such as TP53 and ASXL, were dependent on the status of another cooperating gene (2).

Mutations in NRAS are one of the most common alterations in AML. Moreover, therapies targeting the Ras superfamily, including NRAS mutant AML, have largely failed and this subtype of AML remains challenging to treat. In a recent study of >1,000 cases of AML, mutations in DNA methylation genes, such as TET2, were found to frequently co-occur with NRAS mutations (3). While this may suggest a basis for demethylating treatment in NRAS mutant AML, little is known about the biology or clinical effect of these cooperating mutations.

Objectives:

Using newly developed NRAS mutant AML cells by CRISPR-Cas9 as a basis, novel models of NRAS mutant/methylation gene mutant AML cells will be engineered and characterised in comparison to single mutants and/or wild type cells in terms of basic biology, such as cell cycle, colony formation, induction of apoptosis and DNA damage response. The effect of standard of care induction agents in AML on the novel co-occurring mutant cells will be evaluated. In order to dissect the downstream signalling pathways of the cooperating mutations, RNA-seq will be performed and validated. Using this data, specific genetic vulnerabilities will be identified and investigated. Rational drugs will be tested in both cells and in well-defined AML patient samples, and if applicable, evaluated in vivo with international collaborators.

This studentship will benefit from expertise in AML biology, CRISPR-Cas9 models and drug screening (Matchett) and DNA methylation and advanced genetics/epigenetics (Walsh).

AccessNI clearance required

Please note, the successful candidate will be required to obtain AccessNI clearance prior to registration due to the nature of the project.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

• Sound understanding of subject area as evidenced by a comprehensive research proposal
• Clearly defined research proposal detailing background, research questions, aims and methodology

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Experience using research methods or other approaches relevant to the subject domain
• Sound understanding of subject area as evidenced by a comprehensive research proposal
• Work experience relevant to the proposed project
• Publications record appropriate to career stage
• Experience of presentation of research findings
• A comprehensive and articulate personal statement
• Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

This project is funded by:

• DfE MATCHED

The University offers the following levels of support:

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

• Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
• Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
• Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
• Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies. Further information on cost of living