About the Project
We are looking for an enthusiastic and motivated PhD student to join our expanding research team at Brighton and Sussex Medical School. The candidate will work closely with scientists and clinicians who have extensive expertise in RNA biology, oncogenesis, and myeloma. The focus of the project will be on determining the role of non-coding RNA in myeloma patients who have of an extra copy of the chromosomal 1q region (gain1q).
Multiple Myeloma is a genetically diverse disease characterised by the malignant transformation of antibody secreting plasma cells. It accounts for approximately 10% of haematological malignancies and 2% of all cancers. Despite improvements in therapy and outcome, relapse is almost universal.
We, and others, have previously shown that a key feature of relapse, is the emergence of treatment resistant clones, characterised by the acquisition of new mutations and structural chromosome abnormalities (1 - 3). A key driver of aggressive disease, treatment resistance and clonal evolution is the presence of gain1q (4). Gain(1q) is found in 40% of patients at diagnosis and a greater proportion of patients at relapse. The reasons why gain(1q) leads to a poor prognosis is unknown.
In this project, the successful applicant will determine whether the misexpression of long non-coding RNA impacts on cell biology in patients with and without the presence of gain(1q). We will recruit patients with myeloma who are being treated in East Sussex NHS Trust Hospitals. Ethical approval is already in place and sample biobanking is underway, in preparation for project commencement. There may be the opportunity for the successful candidate to attend the myeloma clinic in Eastbourne Hospital, to gain clinical knowledge and recruit patients.
The successful applicant will learn a broad range of laboratory techniques including, bone marrow sample processing, RNA-seq, qPCR, Western blotting, and cell culture. The student will be based in the Medical Research Building on the University of Sussex Campus, in Brighton. The supervisory team will include Professor Newbury and Dr Towler who have vast experience in RNA stability, Next Generation Sequencing technologies and cancer biology, and Dr Jones, Consultant Haematologist, who has clinical expertise in myeloma and myeloma genetics. In addition, the project will include collaboration with experts based at the University of Arkansas for Medical Science (Professor Michael Bauer) and the University of New York (Professor Gareth Morgan). These centres will provide bioinformatics support and laboratory guidance. If funding allows, the student will be encouraged to visit these centres, to learn novel techniques, bioinformatic programming and to present data.
Ideal candidates will have a strong background in cellular and molecular biology with additional experience of bioinformatics. Eligible candidates will have recently received an MSc and/or a First or 2:1 B.Sc in a relevant subject.
References
1. Jones JR, Weinhold N, Ashby C, Walker BA, Wardell C, Pawlyn C, Rasche L, Melchor L, Cairns DA, Gregory WM, Johnson D, Begum DB, Ellis S, Sherborne AL, Cook G, Kaiser MF, Drayson MT, Owen RG, Jackson GH, Davies FE, Greaves M, Morgan GJ; NCRI Haemato-Oncology CSG. Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients. Haematologica. 2019 Jul;104(7):1440-1450.
2. Jones JR, Barber A, Le Bihan YV, Weinhold N, Ashby C, Walker BA, Wardell CP, Wang H, Kaiser MF, Jackson GH, Davies FE, Chopra R, Morgan GJ, Pawlyn C. Mutations in CRBN and other cereblon pathway genes are infrequently associated with acquired resistance to immunomodulatory drugs. Leukemia. 2021 Oct;35(10):3017-3020.
3. Jones JR, Charlotte Pawlyn, Niels Weinhold, Timothy Cody Ashby, Brian A Walker, Christopher P. Wardell, David Cairns, Walter Martin Gregory, Martin F. Kaiser, Gordon Cook, Mark T Drayson, Roger G Owen, Graham Jackson, Faith E Davies, Gareth J. Morgan, The Impact of gain1q on Mutational Structure and Clonal Evolution in a Uniformly Treated High-Risk Series of Patients at First Relapse, Blood, Volume 138, Supplement 1, 2021, Page 2683, ISSN 0006-4971
4. Weinhold N, Salwender HJ, Cairns DA, Raab MS, Waldron G, Blau IW, Bertsch U, Hielscher T, Morgan GJ, Jauch A, Davies FE, Hänel M, Cook G, Scheid C, Houlston R, Goldschmidt H, Jackson G, Kaiser MF. Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma - a meta-analysis of 2,596 trial patients. Haematologica 2021;106(10):2754-2758; https://doi.org/10.3324/haematol.2021.278888.
5. Pashler, AL, Jones CI, Burgess, T, Towler BP, Newbury SF. (2021) Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identifies disease-relevant transcripts containing G-rich motifs. RNA 10:1265-1280.
6. Towler BP, Pashler AL, Haime HJ, Przybyl KM, Viegas SC, Matos RG, Morley SJ, Arraiano CM, Newbury SF. (2020) Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism. PLoS Genet 16(12): e1009297.
7. Burley TA, Hesketh A, Bucca G, Kennedy E, Ladikou EE, Towler BP, Mitchell S, Smith CP, Fegan C, Johnston R, Pepper A and Pepper C (2022) Elucidation of Focal Adhesion Kinase as a Modulator of Migration and Invasion and as a Potential Therapeutic Target in Chronic Lymphocytic Leukemia. Cancers. 14(7), 1600.
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