Defining the molecular mechanisms of leukaemia chemotherapies

Chemotherapies are usually the backbone of cancer treatment for either curative or palliative patient care. Multiple therapies can be used for the same disease, with the choice of drug dependent on parameters such as the patient’s age and fitness. Therapies can also be changed. For example, after a poor response to one drug or combination a different treatment can be used in an attempt to improve response. Acute myeloid leukaemia (AML) and chronic myelomonocytic leukaemia (CMML) are both managed with drugs that mimic the building blocks of RNA and DNA. Cytarabine, decitabine and azacytidine are all analogues of the canonical cytidine and deoxycytidine nucleotides used for RNA and DNA synthesis. Incorporation of these into RNA or DNA is absolutely essential for their mechanisms of action, yet we do not fully understand this aspect of their drug biology.

Currently, our knowledge of how these drugs function is focused on specific consequences of this misincorporation. This studentship will expand these horizons by taking unbiased approaches to define the fundamental biology of leukaemia drug incorporation into RNA and DNA in detail. We will use innovative technologies applied to clinically relevant model systems and patient samples to define the genomic and transcriptomic loci of drug incorporation. In so doing we will reveal the RNA and DNA synthetic pathways that these drug impact, and test these for their effect on disease biology. Working within an inter-disciplinary team of supervisors, the student will generate complementary datasets using direct RNA and DNA nanopore sequencing and a bespoke methyltransferase tethering method. The RNA and DNA pathways this will identify will be investigated further for their roles in leukaemia biology as well as how these pathways influence the clinical response to each compound. Ultimately, we hope to reveal new means to target the disease through understanding existing chemotherapies.

Research Environment

The student will work across multiple labs as part of an interdisciplinary team gaining knowledge and experience of leukaemia biology as well as advanced molecular techniques. The labs are well funded through the Lister Institute Research Prize Fellowship to John Knight and the Oglesby Leukaemia Research Funding to Kiran Batta and Daniel Wiseman, providing support from a group of 15 researchers including post-docs to fellow PhD students.

Training/techniques provided

The student will gain skills in cell culture, including primary cultures from patients, and advanced molecular techniques to study RNA damage. The project will use cutting edge models of leukaemia as well as innovative applications of native RNA and DNA sequencing techniques, providing the student with a skillset of emerging techniques. The student will gain expertise in these methods by learning from experts from very supportive labs. As well as these practical skills, the student will be trained in experimental planning, project management and scientific dissemination. 

Eligibility 

Candidates are expected to hold (or be about to obtain) a minimum upper second-class honours degree (or equivalent) in a related area / subject. 

Students with experience of studying or working in cancer and/or molecular biology environments, and interest in the molecular mechanisms of disease and drug treatment will be best suited to the project.

How to Apply 

On the online application form select Molecular & Clinical Cancer Sciences

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk.

Equality, Diversity and Inclusion  

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the