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Determining the role of genomic instability in the response of leukaemias to chemotherapies


   Cardiff School of Medicine

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  Prof S Reed, Prof Oliver Ottmann  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Treatment of leukaemia remains a significant challenge primarily due to disease recurrence. Gene mutations present at diagnosis inform clinical risk stratification and type of treatment, while the accumulation of additional genetic lesions accompanies progression of leukaemia. These mutational processes are caused by genomic instability, which is an intrinsic feature of leukaemic cells. Moreover, specific gene mutations themselves are associated with aberrations caused by DNA damage and defective DNA repair, and thus not only function as leukaemic drivers, but also promote leukaemogenesis and clonal evolution. Examples include the BCR-ABL1 translocation and FLT-3 mutations, which are now therapeutically targeted by small molecule kinase inhibitors.

Understanding how DNA damage is generated and repaired depends on the accurate measurement of the frequency and position of DNA double strand breaks (DSBs) throughout the genome. We have developed a novel, method (INDUCE-Seq) to capture DSBs in the genome with exquisite sensitivity. Importantly, this method is capable of simultaneously detecting both rare endogenous ‘background’ breaks in the genome, which can be induced by a variety of normal cellular functions, as well as more abundant targeted breaks, such as those induced by chemotherapy. INDUCE-seq can detect and distinguish between these two events over a broad dynamic range (Dobbs FM et al, doi.org/10.1101/2020.08.25.266239), surpassing all existing cell-based assays and DSB sequencing methodologies in terms of precision, sensitivity, reliability, and throughput. Using this innovative NGS flow cell enrichment method, INDUCE-seq permits the digital detection of DNA breaks in the genome. This makes it possible to simultaneously determine the origins of endogenous ‘background’ breaks in the genome, and differentiates these from aberrantly induced breaks, such as those caused by genomic instability due to defective DNA repair in leukaemic cells (for details see BioRxiv preprint doi: https://doi.org/10.1101/2020.08.25.266239).

 We hypothesize that genomic instability as an intrinsic feature of leukaemic stem cells is a major determinant of response to treatment and response duration, and that the frequency and position of DSBs in the genome will provide predictive and mechanistic information on response or resistance to therapy.

In this project, we will examine the role of genomic instability, as measured by the genome-wide frequency and genomic position of DSBs, in determining the sensitivity of leukaemias to current and experimental therapies and in contributing to leukemic relapse. The differential impact of selective therapies such as kinase inhibitors and conventional cytotoxic chemotherapy on high and low fidelity DNA repair mechanisms and genome-wide distribution of DSBs will be analysed in relation to genetically defined subtypes of leukemia. The impact of these DSB on biological properties and clinical behaviour of leukemic clones will also be explored in phenotypically distinct subpopulations of leukaemic stem cells to gain insights into mechanisms of clonal evolution of leukaemic stem cells as one of the hallmarks of leukaemia progression.

 This project will be conducted in an international collaboration with leading Leukaemia Study Groups, ensuring access to genetically defined, clinically annotated samples from patients with high-risk leukaemias.

Application Process

We are seeking enthusiastic and motivated students with an interest in Cancer or genomic research. Applicants should possess a minimum of an upper second-class Honours degree, master's degree, or equivalent in a relevant subject.

Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

The total duration of this PhD programme is 3.5 years. Following discussion with proposed supervisors and to be considered you must submit a formal application via Cardiff University’s online application service. Medicine - Study - Cardiff University

There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (i.e. April 2022). This will take you to the application portal.

In the ‘Research Proposal’ section of the application enter the name of the project you are applying to.

Candidates must submit the following information:

  • Supporting statement 
  • CV 
  • Qualification certificates 
  • Proof of Funding i.e. a letter of intent from your sponsor or confirmation of self-funded status.
  • References x 2 
  • Proof of English language (if applicable)

Closing date for applicants is 31st March 2022.


Funding Notes

This is a Self-Funded/Sponsored PhD opportunity.
FUNDING REQUIRED:
Full UK/EU or International Tuition Fees
UK Living Expenses
Bench Fees (where applicable)
Open to all students of any nationality without restrictions (UK/EU and International)
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