2. Academic Validation
  3. SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia

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

  • Sci Adv. 2024 Mar 22;10(12):eadl4018. doi: 10.1126/sciadv.adl4018.
Céline Moison 1,  Deanne Gracias 1,  Julie Schmitt 1,  Simon Girard 1,  Jean-François Spinella 1,  Simon Fortier 1,  Isabel Boivin 1,  Rodrigo Mendoza-Sanchez 1,  Bounkham Thavonekham 1,  Tara MacRae 1,  Nadine Mayotte 1,  Eric Bonneil 1,  Mark Wittman 2,  James Carmichael 2,  Réjean Ruel 1,  Pierre Thibault 1 3,  Josée Hébert 1 4 5,  Anne Marinier 1 3,  Guy Sauvageau 1 4 5
Affiliations

Affiliations

  • 1 Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada.
  • 2 Research and Development, Bristol Myers Squibb Company, Cambridge, MA, USA.
  • 3 Department of Chemistry, Université de Montréal, Montréal, Canada.
  • 4 Division of Hematology-Oncology and Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, Canada.
  • 5 Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Canada.
PMID: 38517966 DOI: 10.1126/sciadv.adl4018
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.

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