Cantilena, Sandra;
Gasparoli, Luca;
Pal, Deepali;
Heidenreich, Olaf;
Klusmann, Jan-Henning;
Martens, Joost HA;
Faille, Alexandre;
... de Boer, Jasper; + view all
(2022)
Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.
Clinical and Translational Medicine
, 12
(6)
, Article e933. 10.1002/ctm2.933.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/ctm2.933 |
| Publisher version: | https://doi.org/10.1002/ctm2.933 |
| Language: | English |
| Additional information: | © 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | MLL-fusion, leukaemia, mouse models, precision medicine, targeted therapy, Acute Disease, Apoptosis, Cell Proliferation, Child, Epigenesis, Genetic, Humans, Infant, Leukemia, Oncogene Proteins, Fusion |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10151099 |
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