Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.
Martens, Joost HA
Clin Transl Med
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Cantilena, S., Gasparoli, L., Pal, D., Heidenreich, O., Klusmann, J., Martens, J. H., Faille, A., et al. (2022). Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.. Clin Transl Med https://doi.org/10.1002/ctm2.933
BACKGROUND: Improving the poor prognosis of infant leukaemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven paediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins. METHODS: A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, disulfiram (DSF), based on its efficient ablation of MLL-fusion proteins. The consequences of drug-induced MLL-fusion inhibition were confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and ChIP-qPCR and ChIP-seq analysis. All statistical tests were two-sided. RESULTS: Drug-induced inhibition of MLL-fusion proteins by DSF resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukaemia progression in vivo. Mechanistically, DSF abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukaemic programmes setup by the MLL-fusion protein. CONCLUSION: DSF can directly inhibit MLL-fusion proteins and demonstrate antitumour activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly targets the initiating oncogenic MLL-fusion protein.
Blood Cancer UK (21002)
Wellcome Trust (100140/Z/12/Z)
External DOI: https://doi.org/10.1002/ctm2.933
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337999
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/