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

Oncotarget. 2016 Nov 29;7(48):79722-79735. doi: 10.18632/oncotarget.12944.

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.

Keywords: differentiation therapy; glutamine; leukemia; metabolism; microenvironment.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzeneacetamides / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Energy Metabolism / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Glutamate Dehydrogenase / antagonists & inhibitors
  • Glutamate Dehydrogenase / genetics
  • Glutamate Dehydrogenase / metabolism
  • Glutamic Acid / metabolism
  • Glutaminase / antagonists & inhibitors*
  • Glutaminase / genetics
  • Glutaminase / metabolism
  • Glutamine / metabolism*
  • Glutarates / metabolism
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Mutation
  • Protein Isoforms
  • Sulfides / pharmacology*
  • Thiadiazoles / pharmacology*

Substances

  • Antineoplastic Agents
  • Benzeneacetamides
  • CB-839
  • Enzyme Inhibitors
  • Glutarates
  • Protein Isoforms
  • Sulfides
  • Thiadiazoles
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
  • Glutamine
  • alpha-hydroxyglutarate
  • Glutamic Acid
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human
  • Glutamate Dehydrogenase
  • GLUD1 protein, human
  • GLS1 protein, human
  • Glutaminase