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

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

Author information

1
Institut 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;
2
Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France;
3
Institut 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; Service d'Hématologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
4
INSERM U699, Faculté de Médecine Xavier Bichat, Paris, France; and.
5
Institut 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; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
6
Calithera Biosciences, South San Francisco, CA.

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.

PMID:
26186940
PMCID:
PMC4608389
DOI:
10.1182/blood-2015-01-621870
[Indexed for MEDLINE]
Free PMC Article

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