Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells.

Abstract

Approximately 20% of acute myeloid leukemia (AML) patients carry mutations in IDH1 or IDH2 that result in over-production of the oncometabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission; however, almost all patients eventually acquire drug resistance and relapse. Using a multi-allelic mouse model of IDH1-mutant AML, we demonstrate that the clinical IDH1 inhibitor AG-120 (ivosidenib) exerts cell-type-dependent effects on leukemic cells, promoting delayed disease regression. Although single-agent AG-120 treatment does not fully eradicate the disease, it increases cycling of rare leukemia stem cells and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitizes IDH1-mutant AML to azacitidine, with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide a mechanistic rationale for the observed combinatorial effect of AG-120 and azacitidine in patients.

• Authors: Emily Gruber, Joan So, Alexander C Lewis, Rheana Franich, Rachel Cole, Luciano G Martelotto, Amy J Rogers, Eva Vidacs, Peter Fraser, Kym Stanley, Lisa Jones, Anna Trigos, Niko Thio, Jason Li, Brandon Nicolay, Scott Daigle, Adriana E Tron, Marc L Hyer, Jake Shortt, Ricky W Johnstone, Lev M Kats
• Journal: Cell reports (Cell Rep) Vol. 40 Issue 7 Pg. 111182 (08 16 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35977494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Isocitrate Dehydrogenase
• Azacitidine

Topics

• Animals
• Azacitidine (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Isocitrate Dehydrogenase (genetics, metabolism)
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Mice
• Mutation (genetics)
• Stem Cells (metabolism)