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

Gruber, E; So, J; Lewis, AC; Franich, R; Cole, R; Martelotto, LG; Rogers, AJ; Vidacs, E; Fraser, P; Stanley, K; Jones, L; Trigos, A; Thio, N; Li, J; Nicolay, B; Daigle, S; Tron, AE; Hyer, ML; Shortt, J; Johnstone, RW; Kats, LM

Author(s): Gruber, E; So, J; Lewis, AC; Franich, R; Cole, R; Martelotto, LG; Rogers, AJ; Vidacs, E; Fraser, P; Stanley, K; Jones, L; Trigos, A; Thio, N; Li, J; Nicolay, B; Daigle, S; Tron, AE; Hyer, ML; Shortt, J; Johnstone, RW; Kats, LM;
Details: Publication Year 2022-08-16,Volume 40,Issue #7,Page 111182
Journal Title: Cell Reports
Publication Type: Research article
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.
Keywords: Animals; Azacitidine/pharmacology; Enzyme Inhibitors/pharmacology; *Isocitrate Dehydrogenase/genetics/metabolism; *Leukemia, Myeloid, Acute/drug therapy/genetics; Mice; Mutation/genetics; Stem Cells/metabolism; 2-hg; CP: cancer; Idh1; ivosidenib; leukemia stem cells; non-genetic heterogeneity; pyrimidine salvage
Department(s): Laboratory Research
PubMed ID: 35977494
Publisher's Version: https://doi.org/10.1016/j.celrep.2022.111182
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2022.111182
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-11-01 12:10:45

Last Modified: 2024-11-01 12:11:37