Cantilena, Sandra, Gasparoli, Luca, Pal, Deepali, Heidenreich, Olaf, Klusmann, Jan‐Henning, Martens, Joost H. A., Faille, Alexandre, Warren, Alan J., Karsa, Mawar, Pandher, Ruby, Somers, Klaartje, Williams, Owen and de Boer, Jasper (2022) Direct targeted therapy for MLL‐fusion‐driven high‐risk acute leukaemias. Clinical and Translational Medicine, 12 (6). e933. ISSN 2001-1326
|
Text
Clinical Translational Med - 2022 - Cantilena - Direct targeted therapy for MLL‐fusion‐driven high‐risk acute leukaemias.pdf - Published Version Available under License Creative Commons Attribution 4.0. Download (3MB) | Preview |
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.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding information: This work was supported by grants from the Alternative Hair Charitable Foundation, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund and Leukaemia UK. SC was funded by a project grant from Leukaemia UK (PG17-001), OW and JdB by Action Medical Research/Life Arc (GN2820), OW by the MRC (MR/S021000/1), LG by Children with Cancer UK (14-169, 17-249). JHK is a grantee of the European Research Council (Grant agreement no. 714226) and a recipient of the St. Baldrick's Robert J. Arceci Innovation Award. AJW was supported by the UK Medical Research Council (MR/T012412/1), a Wellcome Trust strategic award to the Cambridge Institute for Medical Research (100140) and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. A special thank you is given to Tony and Maggie Rizzo for their support in this project. |
| Uncontrolled Keywords: | leukaemia, MLL-fusion, mouse models, precision medicine, targeted therapy |
| Subjects: | A300 Clinical Medicine C700 Molecular Biology, Biophysics and Biochemistry |
| Department: | Faculties > Health and Life Sciences > Applied Sciences |
| Depositing User: | Elena Carlaw |
| Date Deposited: | 22 Jul 2022 12:46 |
| Last Modified: | 22 Jul 2022 13:00 |
| URI: | http://nrl.northumbria.ac.uk/id/eprint/49596 |
Actions (login required)
 |
View Item |
Downloads
Downloads per month over past year
