Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth

Abstract

Leukemia cells are described as a prototype of glucose-consuming cells with a high turnover rate. The role of glutamine in fueling the tricarboxylic acid cycle of leukemia cells was however recently identified confirming its status of major anaplerotic precursor in solid tumors. Here we examined whether glutamine metabolism could represent a therapeutic target in leukemia cells and whether resistance to this strategy could arise. We found that glutamine deprivation inhibited leukemia cell growth but also led to a glucose-independent adaptation maintaining cell survival. A proteomic study revealed that glutamine withdrawal induced the upregulation of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT), two enzymes of the serine pathway. We further documented that both exogenous and endogenous serine were critical for leukemia cell growth and contributed to cell regrowth following glutamine deprivation. Increase in oxidative stress upon inhibition of glutamine metabolism was identified as the trigger of the upregulation of PHGDH. Finally, we showed that PHGDH silencing in vitro and the use of serine-free diet in vivo inhibited leukemia cell growth, an effect further increased when glutamine metabolism was blocked. In conclusion, this study identified serine as a key pro-survival actor that needs to be handled to sensitize leukemia cells to glutamine-targeting modalities.

α-Ketothioamide Derivatives: A Promising Tool to Interrogate Phosphoglycerate Dehydrogenase (PHGDH)

“…Protein extraction and Western blot analysis were carried out as reported elsewhere (Polet et al 11 ).…”

Metabolic dependencies and vulnerabilities in leukemia

“…Notably, AML leukemia-initiating cells are particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment and AMPK inhibition synergizes with dietary restriction to suppress leukemogenesis (Saito et al 2015). In addition, it should be considered that diet may affect the activity and antileukemic effects of metabolic drugs and targeted therapies as a result of the replenishment of metabolic pathways (Polet et al 2016) and signaling feedback mechanisms (Hopkins et al 2018), respectively. The effects of diet in therapy response is exemplified by the impact of ketogenic diet on the effect of PI3K inhibitor in AML (Hopkins et al 2018).…”

Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche

“…For example, hypoxia-induced factor 1a (HIF1A) is required for the maintenance of glycolytic status and activities of LICs (Wang et al, 2011), and depletion of two key catalytic enzymes for glycolysis including lactate dehydrogenase A (LDHA) and pyruvate kinase muscle isozyme M2 (PKM2) significantly delays leukemia development . Other glycolysis-related enzymes, such as 3-phosphoglycerate dehydrogenase (Polet et al, 2016) and glucose transport protein 1 (GLUT1) (Siska et al, 2016), are also important for leukemogenesis. However, studies from Lagadinou et al (2013) suggest that oxidative phosphorylation is indispensable for the maintenance of human quiescent LICs.…”