Pre‐Clinical Evaluation of Drug Induced Proteolysis of MLL‐Fusions in Acute Leukemia

Abstract

The mixed‐lineage leukemia (MLL) gene is often susceptible to chromosomal rearrangements in pediatric leukemias. The resulting chimeric proteins are a product of reciprocal translocations between the gene and various fusion partners. In MLL‐rearranged leukemia, these fusion proteins drive leukemogenesis by interfering with transcriptional elongation to deregulate target gene expression. MLL fusion proteins, indicative of a more aggressive disease, are responsible for a large proportion of acute infant leukaemias. Therapeutic methods to target oncogenic fusion proteins, such as PML‐RARA, have proven pharmacologically achievable and highly successful. For this purpose, our lab has established a drug screening program using in cellulo bio‐luminescence with the objective of repositioning drugs that cause MLL‐fusion protein degradation. Compounds that produced a 30% reduction in MLL fusion protein expression via two different screening methods, luminescence and western blotting, were considered positive hits. In this present study I validate and characterize one of these positive hits. Upon treatment of MLL‐rearranged cell lines, the compound was capable of ablating MLL fusion protein expression resulting in the down regulation of target gene HOXA10. Furthermore, treatment caused loss of leukaemic stem cell activity via induction of cell death and inhibition of self‐renewal capacity. To further analyze the mechanism of this compound, RNA‐sequencing and Gene Set Enrichment Analysis will be performed to identify gene sets associated with the disease treated phenotype. Overall this study identifies a potential repurposed therapeutic for the treatment of MLL‐rearranged leukaemias.Support or Funding InformationThis work was supported by the UCL Child Health Research Studentship.