Acute myeloid leukaemia (AML), the most common acute leukemia in adults, accounts for ~3000 cases per year in the UK. Abnormal accumulation of blasts in the bone marrow (BM) due to either excessive proliferation or survival and impaired differentiation characterizes the clinical picture of AML of anemia, increased infection, and bleeding.
Patients with high-risk AML have a poor prognosis with an overall survival below 30% at five years (Grimwade2010). In addition, more than 50% of high-risk AMLs are associated with mutations within critical RNA processing and chromatin modelling factors, creating the so-called chromatin/spliceosome group of AML (Doehner2017).
Aberrant RNA processing not only includes splicing but also leads to disturbed processes that bridge into the unknown world of non-coding RNAs with many functions still to be explored. For example, the lncRNA HOTAIRM1 and several microRNAs (miRs)(e.g., miR-p196b) represent independent prognostic factors (DiazBeya2015).
Chromatin modelling consists of histone modifications by post-translational modifications (acetylation, methylation, or phosphorylation) that changes the regulation and accessibility of the chromatin to transcription.
Studying the mechanisms by which these mutations induce high-risk AML creates experimental evidence for developing novel targeted therapy options. We recently have shown that therapy resistance in high-risk AML is closely associated with aberrant RNA processing and chromatin modelling. Moreover, now to investigate signalling pathways and activation of proteins/peptides in primary samples, we analysed a phospho-proteomics dataset of high-risk AML patients by bioinformatics. This analysis suggested a close relationship between aberrant RNA processing and impaired chromatin modelling responsible for aberrant DNA damage and repair (DDR) mechanisms, responsible for the therapy resistance in these subtypes of AML (Chiriches2022; Chiriches manuscript in preparation).
Therefore we have the following aims:
· Which are the factors determining the aberrant RNA processing and chromatin modelling, and what are the consequences of their targeting?
· How are aberrant chromatin modelling and RNA processing connected with DDR in AML?
· How can pharmacological targeting of aberrant RNA processing (e.g., METTL3 inhibition) or chromatin modelling influence the outcome in high-risk AML?
Technologies like digital PCR, proteomics and phospho-proteomics, next-generation sequencing, CRISPR-CAS9, and bioinformatics will answer these questions. We will use several high-risk AML models, including primary and retrovirally infected cells and cell lines.
The clinical significance of this project is a better understanding of resistance mechanisms in AML which most likely are active in other subtypes of blood cancer and other types of cancer. In addition, our results will create a springboard for further basic and clinical investigations, including clinical trials increasing the precision of therapeutic intervention and prevention not only in AML but also as a paradigm for other cancers.
Entry Requirements
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).
How to Apply
This studentship has a start date of April 2023. In order to be considered you must submit a formal application via Cardiff University’s online application service.
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’ (April 2023). This will take you to the application portal.
In order to be considered candidates must submit the following information:
• Supporting statement
• CV
• Qualification certificates
• References x 2
• Proof of English language (if applicable)
International applicants are welcomed if the difference in fees can be covered.
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