Acute myeloid leukemia (AML) remains difficult to treat because of high genetic heterogeneity not only between different patients but also between subclonal populations of cancer cells within the same patient. Despite advances in knowledge, understanding the metabolic signature of the cells that change in this disease is one of the scientific challenges in designing more effective therapies.
Now, in a new study, researchers from research institutions such as the University of Groningen in the Netherlands and the University of Barcelona in Spain have found that a key enzyme in glucose metabolism, pyruvate dehydrogenase kinase 1 (PDK1), is a key enzyme in leukemia stem cells containing a large number of leukemia stem cells. , overexpressed in AML patients without mutations in the FTL3 and NPM1 genes (especially the relevant mutations in the AML patient classification). The findings were recently published in the journal of Nature Communications.
PDK1: a determinant of different metabolic states
In the new study, PDK1 was identified as a determinant of different metabolic states. “PDK1 plays a decisive role in energy metabolism, as it is the key to closing the door to mitochondrial metabolism through phosphorylation and subsequent inhibition of pyruvate dehydrogenase (PDH),” said co-author Professor Marta Cascante from the University of Barcelona.
The researchers applied metabolomic, proteomic, genomic and transcriptomic techniques, as well as gene ontology and gene set enrichment analysis (GSEA), among others. According to their conclusions, in leukemia stem cells, PDK1 prevents pyruvate from entering mitochondria (the organelle responsible for cellular energy production) as a metabolic fuel for cellular glycolysis. This altered metabolic pathway produces lactate, which helps establish the typical phenotype of cancer cells.
These findings also indicate that inhibition of PDK1 induces mitochondrial stress and improves the efficacy of glutaminase inhibitor-based antitumor therapies.