Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations

• Published in: Experimental hematology 2014-04, Vol.42 (4), p.247-251
• Main Authors: Emadi, Ashkan, Jun, Sung Ah, Tsukamoto, Takashi, Fathi, Amir T, Minden, Mark D, Dang, Chi V
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Female; Glutaminase - antagonists & inhibitors; Glutaminase - genetics; Glutaminase - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Male; Mutation; Sulfides - pharmacology; Thiadiazoles - pharmacology
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2013.12.001

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.