Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Blood. 2015 Sep 10;126(11):1346-56. doi: 10.1182/blood-2015-01-621870. Epub 2015 Jul 17.

Abstract

Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzeneacetamides / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Citric Acid Cycle / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gene Knockdown Techniques
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / genetics
  • Glutaminase / metabolism
  • Glutamine / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Mitochondria / metabolism
  • Oxidative Phosphorylation / drug effects
  • Oxygen Consumption / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Sulfonamides / pharmacology
  • Thiadiazoles / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzeneacetamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • CB-839
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Thiadiazoles
  • Glutamine
  • GLS protein, human
  • Glutaminase
  • venetoclax