Acute myeloid leukaemia (AML) is a clonal disorder of haematopoietic stem/progenitor cells, which acquire mutations to form leukaemic stem cells (LSCs) that fuel the disease. Since current therapies fail to eradicate disease-causing LSCs, which also fuel devastating disease relapses, it is essential to identify therapeutic targets for LSC elimination. Significantly, emerging research has placed RNA modifications as key regulators of cancer formation. In fact, our studies revealed that mRNA N6-methyladenosine (m6A) modification, whose function is executed by the m6A reader YTHDF2 that promotes mRNA decay, plays an essential role in AML, specifically compromising LSCs (Paris et al, Cell Stem Cell, 2019). Moreover, we also discovered that deletion of uridylyl-transferases which uridylate mRNA polyA tails, thus promoting their decay, disables LSCs. Therefore, inhibition of YTHDF2- and uridylation-mediated RNA degradation may offer unprecedented therapeutic value in treating AML.
We hypothesise that uridylation- and m6A-depended RNA decay pathways are promising therapeutic targets in AML. Firstly, we will reveal whether targeting uridylation eliminates LSCs. Secondly, we shall dissect the mechanisms through which uridylation may drive AML propagation. Finally, we will determine whether uridylation and YTHDF2 control overlapping or distinct transcripts for degradation, and reveal the novel therapeutic value of their inhibition in AML. This project will unveil and functionally explore the translational potential of inhibiting mRNA decay pathways to specifically eradicate LSCs.
All applicants should have or be expecting:
- A first or upper second class honours degree in a relevant biological subject from a UK university or the international equivalent from a recognised institution. Or,
- A medical degree from a recognised institution.
If your degree has not yet been awarded but you are expected to meet the above entry requirements, you are welcome to apply.
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