title: Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations.
abstract: The incidence of mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in de novo acute myeloid leukemia (AML) is approximately 20%. These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for α-ketoglutarate, which is consumed by leukemia cells to produce a cancer-derived metabolite, 2-hydroxyglutarate. We sought to exploit this glutamine addiction therapeutically in mutant IDH primary AML cells from patients by measuring cell growth after exposure to a small molecule glutaminase inhibitor, BPTES. We found that BPTES only suppressed the growth of AML cells expressing mutant IDH compared with those expressing wild type IDH. This study lays the groundwork for strategies to target a specific subtype of AML metabolically with IDH mutations with a unique reprogramming of intermediary metabolism that culminates in glutamine dependency of cancer cells for survival.
authors: University of Maryland, School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD. Electronic address: aemadi@umm.edu.
authors: Ashkan
authors: A
authors: Emadi
authors: Institute of Medical Science, University of Toronto, Toronto, Canada.
authors: Sung Ah
authors: SA
authors: Jun
authors: Brain Science Institute, Johns Hopkins University, Baltimore, MD.
authors: Takashi
authors: T
authors: Tsukamoto
authors: Department of Hematology and Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: Amir T
authors: AT
authors: Fathi
authors: Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada.
authors: Mark D
authors: MD
authors: Minden
authors: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
authors: Chi V
authors: CV
authors: Dang
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D009154:Mutation; D013440:Sulfides / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D005972:Glutaminase