Journal article
Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells
E Gruber, J So, AC Lewis, R Franich, R Cole, LG Martelotto, AJ Rogers, E Vidacs, P Fraser, K Stanley, L Jones, A Trigos, N Thio, J Li, B Nicolay, S Daigle, AE Tron, ML Hyer, J Shortt, RW Johnstone Show all
Cell Reports | CELL PRESS | Published : 2022
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 ..
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Awarded by Amgen
Funding Acknowledgements
We thank members of the molecular genomics, animal, and flow cytometrycore facilities at the Peter MacCallum Cancer Centre for technical support;Brian Liddicoat for assistance with bisulfite sequencing; and Dylan Marchioneand Emma Dion for critical review of the manuscript. This work was supportedby a research grant from the National Health and Medical Research Council of Australia (APP1099160). The following authors were supported by fellowships:L.M.K. from the Victorian Cancer Agency (MCRF15003), A.C.L. from the Brazisfamily, J.S. from the Medical Research Future Fund of Australia(GNT1160133), and L.G.M. from The Lorenzo and Pamela Galli Medical Research Trust. E.G. was supported by the Australian Postgraduate Award.