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

Menée in vitro et in vivo, cette étude française met en évidence des mécanismes suggèrant l'intérêt de développer des inhibiteurs de la glutaminase C pour le traitement, en combinaison avec un inhibiteur de BCL-2, des patients atteints d'une leucémie myéloïde aiguë

Résumé en anglais

Genetic or compound CB-839-induced GAC inhibition reduces OXPHOS and has antileukemic activity in AML.GAC inhibition synergizes with BCL-2 inhibition by compound ABT-199. 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 AML cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacological 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, a GLS1-knockdown dramatically inhibited AML development in NSG mice. The anti-leukemic activity of CB-839 was abrogated by both the expression of a hyperactive GACK320A allele and the addition of the TCA 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.