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A new strategy based on copper overdose to treat AML
Published on March 25, 2024
Despite the therapeutic advances of recent years in the treatment of acute myeloid leukemia (AML), this pathology remains associated with a poor prognosis. In a new study, the Leucegene group led by Guy Sauvageau, Director of IRIC’s Molecular Genetics of Stem Cells Research Unit, Anne Marinier, Director of IRIC’s Drug Discovery Unit, and Josée Hébert (Banque de cellules leucémiques du Québec (BCLQ), Maisonneuve-Rosemont Hospital Research Center) proposes a therapeutic strategy based on copper overdose as a treatment for a genetic subgroup of AML particularly sensitive to this approach. Led by Céline Moison and Deanne Gracias (biology), and Julie Schmitt and Réjean Ruel (chemistry), in collaboration with the BCLQ genetics laboratory team, this project has been published in the prestigious journal Science Advances.
UM4118: inducing cell death through copper regulation
The research team tested a library of 10,000 small molecules on 56 samples of AML patients collected and characterized by BCLQ, in order to identify new therapeutic strategies for this cancer. The results obtained led to the identification of a molecule that selectively inhibits the growth of leukemia cells, and more specifically cells with mutations in the SF3B1 (splicing factor 3b subunit 1) gene, associated with a poor prognosis in AML.
The chemist Julie Schmitt has optimized the identified molecule to make it more potent and selective, while being less genotoxic. The UM4118 molecule designed in this way acts as a copper ‘ionophore’: it can bind this metal, transport it into cells and thus disrupt cellular copper homeostasis. This inhibits the mitochondrial respiratory chain and causes copper-dependent cell death, recently described as cuproptosis.
A new precision therapy for a genetic group at high risk of AML
The team also demonstrated that AML with mutations in the SF3B1 gene are more sensitive to UM4118-mediated cuproptosis. Indeed, these mutations alter the expression of the mitochondrial transporter ABCB7, which accentuates the effect of the UM4118 molecule.
In addition to identifying a biomarker for the potential use of copper ionophores as an anti-tumor strategy, this study provides a better understanding of the cell death mechanism of cuproptosis, with a view to exploiting it for the treatment of poor-prognosis AML.
The team recently received funding from the Richard and Edith Strauss Foundation to further develop the UM4118 molecule as a novel therapeutic agent for AML, an approach that could potentially be applied to other pathologies.
Cited study
Moison C, Gracias D, Schmitt J, Girard S, Spinella J-F, Fortier S, Boivin I, Mendoza-Sanchez R, Thavonekham B, MacRae T, Mayotte N, Bonneil E, Wittman M, Carmichael J, Ruel R, Thibault P, Hébert J, Marinier A, Sauvageau G. SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia. Science Advances, 2024. DOI: 10.1126/sciadv.adl4018
