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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition
Nathalie Jacque1, Anne Marie Ronchetti1, Clément Larrue2
1Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
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.
Insights
Targeting glutaminase (GLS1) in acute myeloid leukemia (AML) cells inhibits mitochondrial respiration, halting cancer growth and inducing apoptosis. This GLS1 inhibition shows promise as a novel therapeutic strategy for AML.
Area of Science:
- Metabolic pathways in cancer
- Cancer cell metabolism
- Hematologic malignancies
Background:
- Cancer cells exhibit increased biosynthetic demands, relying on glutamine.
- Glutamine catabolism, limited by glutaminase (GA), is crucial for cancer cell adaptation.
- Specific GA isoforms, GLS1 and GLS2, are encoded by distinct human genes.
Purpose of the Study:
- To investigate the role of glutamine metabolism in acute myeloid leukemia (AML) cell bioenergetics.
- To evaluate GLS1 as a therapeutic target in AML.
- To explore the effects of GLS1 inhibition on mitochondrial oxidative phosphorylation (OXPHOS) and leukemic cell survival.
Main Methods:
- Investigated glutamine levels' control over mitochondrial oxidative phosphorylation (OXPHOS) in AML cells.
- Utilized GLS1 gene knockdown and pharmacologic inhibition with CB-839.
- Assessed leukemic cell proliferation, apoptosis, and in vivo AML development in NSG mice.
- Examined the effects of GAC(K320A) allele expression and α-ketoglutarate addition.
- Evaluated glutaminolysis inhibition in combination with BCL-2 inhibitor ABT-199.
Main Results:
- Glutaminase C (GAC), the predominant GA isoform in AML, was identified.
- GLS1 knockdown and CB-839 treatment reduced OXPHOS, arrested proliferation, and induced apoptosis in AML cells without harming normal progenitors.
- GLS1 inhibition significantly inhibited AML development in vivo.
- Antileukemic effects were linked to GLS1's role in AML cell survival, as evidenced by abrogation with GAC(K320A) and α-ketoglutarate.
- Glutaminolysis inhibition synergized with ABT-199, enhancing leukemic cell apoptosis.
Conclusions:
- Glutamine addiction, mediated by GLS1, is critical for AML cell survival and OXPHOS.
- Targeting GLS1 represents a potential novel therapeutic strategy for AML.
- Combined inhibition of glutaminolysis and BCL-2 may offer synergistic therapeutic benefits in AML treatment.
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