Cantilena, Sandra; (2018) Drug induced degradation of driver proteins: A novel approach to target MLL-fusions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Acute leukaemias in infants are associated with inferior outcomes. The majority of infant acute leukaemia is characterized by balanced chromosomal translocations involving the mixed lineage leukaemia (MLL) gene. Previous work in the department established that the novel formed MLL fusions are the proto-oncoproteins responsible for leukaemia initiation and maintenance so that inhibition of MLL-fusions, in conditional mouse models, resulted in complete disease remission. Therefore, a therapy that inactivates the MLL fusion protein, by protein degradation for example, would offer new hope to these patients. The aim of this study is to identify clinically approved drugs that are capable of inducing degradation of MLL leukaemic fusion proteins. An indicator cell line consisting of a THP1 cell clone expressing firefly luciferase fused to the MLL-AF9 protein, combined with renilla luciferase, was used to screen a collection of 1,280 approved drugs for their ability to induce proteolysis of MLL fusion proteins. 25 drugs lowered the luciferase to renilla ratio, of which 3 were confirmed by western blotting to decrease MLL-fusion protein levels. One drug was taken forward for further analysis. This drug was able to induce the proteolysis of various MLL fusion proteins in human MLL rearranged cell lines and primary patient material. Transcriptome profiling showed shut down of the MLL-fusion signature within 16hrs of addition of the drug. Proteolysis of MLL fusion proteins should also result in a block in self-renewal, as was previously shown in the conditional mouse model. While the drug had no significant impact on the colony formation of normal haematopoietic progenitor cells, it was able to block the colony formation ability of MLL rearranged cell lines. Finally, global alterations in the epigenetic landscape following drug treatment were analysed. This study highlights a new approach to identifying drugs that block driver oncogenes and has identified a potential novel treatment for a major subtype of acute leukaemias in infants.

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