BSc (with distinction)
Masters by Research in Oncology
In-frame translocations of the MLL gene produces more than 120 different MLL fusion proteins (MLL-FPs). MLL-FPs are potent oncoproteins that are thought to be the main drivers of a set of aggressive acute leukemias as patients carry very few additional mutations. Despite much progress in the treatment of childhood leukemias, children carrying MLL rearrangements have a very poor survival prognosis, even with the advent of novel therapeutic approaches such as CAR-T cell therapy, thus treatment of MLL leukemias remains an unmet need. MLL and the MLL-FP MLL-AF4 have previously been shown to bind to telomeres, with loss of MLL associated with increases in telomeric transcription and associated telomeric DNA damage.
Telomeres are short sequences (TTAGGG) found at the ends of chromosomes protect DNA from shortening after each cell cycle division. Once DNA shortens significantly, the cell is no longer able to keep dividing resulting in senescence. In order to escape senesence cancers must utilise pathways for maintaining their telomeres. This can be done by one of two methods, by upregulating telomerase (an enzyme that maintains telomere lengths) or through a telomerase independent mechanism - the Alternative Lengthening of Telomeres( ALT) pathway.
My goal is to explore how the wild type and fusion protein found in these leukemias interact with the telomeric machinery and how this may affect telomere maintenance and stability in these cancers.
The second aspect of my research is to generate a phenotypic profile of MLL-AF4 leukemias based on their surface protein and mRNA expression using Cellular Indexing of Transcriptome and Epitopes by sequencing (CITE-seq).This will allow us to futher understand the nature of these leukemias and the process involved in the cells transforming.