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Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells.
Gruber, Emily; So, Joan; Lewis, Alexander C; Franich, Rheana; Cole, Rachel; Martelotto, Luciano G; Rogers, Amy J; Vidacs, Eva; Fraser, Peter; Stanley, Kym; Jones, Lisa; Trigos, Anna; Thio, Niko; Li, Jason; Nicolay, Brandon; Daigle, Scott; Tron, Adriana E; Hyer, Marc L; Shortt, Jake; Johnstone, Ricky W; Kats, Lev M.
  • Gruber E; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • So J; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Lewis AC; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Franich R; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Cole R; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Martelotto LG; The University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, VIC 3052, Australia.
  • Rogers AJ; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Vidacs E; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Fraser P; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Stanley K; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Jones L; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Trigos A; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Thio N; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Li J; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Nicolay B; Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
  • Daigle S; Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA; Servier Pharmaceuticals, Boston, MA 02210, USA.
  • Tron AE; Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA; Servier Pharmaceuticals, Boston, MA 02210, USA.
  • Hyer ML; Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA; Servier Pharmaceuticals, Boston, MA 02210, USA.
  • Shortt J; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3068, Australia; Monash Haematology, Monash Health
  • Johnstone RW; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Kats LM; The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia. Electronic address: lev.kats@petermac.org.
Cell Rep ; 40(7): 111182, 2022 08 16.
Article en En | MEDLINE | ID: mdl-35977494
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Isocitrato Deshidrogenasa Límite: Animals Idioma: En Año: 2022 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Isocitrato Deshidrogenasa Límite: Animals Idioma: En Año: 2022 Tipo del documento: Article