Inhibiting glutaminase in acute myeloid leukemia: Metabolic dependency of selected AML subtypes

Polina Matre, Juliana Velez, Rodrigo Jacamo, Yuan Qi, Xiaoping Su, Tianyu Cai, Steven M. Chan, Alessia Lodi, Shannon R. Sweeney, Helen Ma, Richard Eric Davis, Natalia Baran, Torsten Haferlach, Xiaohua Su, Elsa Renee Flores, Doriann Gonzalez, Sergej Konoplev, Ismael Samudio, Courtney DiNardo, Ravi MajetiAaron D. Schimmer, Weiqun Li, Taotao Wang, Stefano Tiziani, Marina Konopleva

    Research output: Contribution to journalArticlepeer-review

    139 Scopus citations

    Abstract

    Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes.

    Original languageEnglish (US)
    Pages (from-to)79722-79735
    Number of pages14
    JournalOncotarget
    Volume7
    Issue number48
    DOIs
    StatePublished - 2016

    Keywords

    • Differentiation therapy
    • Glutamine
    • Leukemia
    • Metabolism
    • Microenvironment

    ASJC Scopus subject areas

    • Oncology

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