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Publication — IRIC

SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia.

In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward SF3B1-mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter ABCB7 is synthetic lethal to UM4118. ABCB7 is misspliced and down-regulated in SF3B1-mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued SF3B1-mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of SF3B1-mutated AMLs. We thus propose SF3B1 mutations as a biomarker for future copper ionophore-based therapies.

Publication date
March 22, 2024
Principal Investigators
Moison C, Gracias D, Schmitt J, Girard S, Spinella JF, 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
PubMed reference
Sci Adv 2024;10(12):eadl4018
PubMed ID
Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada.