<i>SF3B1</i> mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia
Céline Moison, Deanne Gracias, Julie Schmitt, Simon Girard, Jean-François Spinella, Simon Fortier, Isabel Boivin, Rodrigo Mendoza‐Sanchez, Bounkham Thavonekham, Tara MacRae, Nadine Mayotte, Éric Bonneil, Mark D. Wittman, James Carmichael, Réjean Ruel, Pierre Thibault, Josée Hébert, Anne Marinier, Guy Sauvageau
Abstract
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.