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

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

Author information

1
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
4
Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.
5
Lymphoma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
CEO of MLL Munich Leukemia Laboratory, Munich, Germany.
7
Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9
The Centre for Drug Research and Development Biologics, Vancouver, British Columbia, Canada.
10
Medical Biophysics, Princess Margaret Hospital / Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
11
Analytical Chemistry, Pharmacology, Spectroscopy, Calithera Biosciences, South San Francisco, CA, USA.

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

PMID:
27806325
PMCID:
PMC5340236
DOI:
10.18632/oncotarget.12944
[Indexed for MEDLINE]
Free PMC Article

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