Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells

Cancer Cell. 2018 Nov 12;34(5):724-740.e4. doi: 10.1016/j.ccell.2018.10.005.


In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death. In contrast, LSCs obtained from relapsed AML patients are not reliant on amino acid metabolism due to their ability to compensate through increased fatty acid metabolism. These findings indicate that clinically relevant eradication of LSCs can be achieved with drugs that target LSC metabolic vulnerabilities.

Keywords: acute myeloid leukemia; amino acids; cancer cell metabolism; leukemia stem cells; metabolomics; venetoclax.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Azacitidine / pharmacology
  • Biological Transport / drug effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Fatty Acids / metabolism*
  • Female
  • Glycolysis / physiology
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology*
  • Lipid Metabolism / drug effects
  • Metabolome / physiology
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Oxidative Phosphorylation / drug effects*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Sulfonamides / pharmacology


  • Amino Acids
  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Fatty Acids
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Azacitidine
  • venetoclax