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Rebecca Olin, MD, MS


Heterogeneous Landscape of AML: Focus on PDK1 Activity Among Subtypes

By: Lauren Harrison, MS
Posted: Tuesday, May 17, 2022

In a study published in Nature Communications, pyruvate dehydrogenase kinase 1 (PDK1) was identified as a targetable determinant of different metabolic states in acute myeloid leukemia (AML). Specifically, PDK1 was noted to be overexpressed in patients with AML who have a high number of leukemic stem cells and lack mutations in FTL3 and NPM1 genes. Jan Jacob Schuringa, PhD, of the University Medical Center Groningen in Groningen, the Netherlands, was a part of the team that conducted this research.

“PDK1 plays a determining role in the energy metabolism, because it is the key that closes the entrance door to the mitochondrial metabolism through the phosphorylation and the later inhibition of the pyruvate dehydrogenase enzyme (PDH),” said coauthor Marta Cascante, PhD, of the University of Barcelona, in an institutional press release.

The researchers used a combination of in vivo assays including cell culturing and xenograft models, as well as metabolomic, proteomic, genomic, and transcriptomic techniques in their study. They found that AML cells demonstrate heterogeneity in their metabolic signatures when compared with healthy hematopoietic stem cells. Upregulated proteins included several that are a part of the electron transport chain plus PDK1, indicating opposing phenotypes in glucose metabolism. PDK1 was further investigated and was noted to reduce oxidative respiration activity in the AML cells, where it was highly expressed.

Different AML subtypes demonstrated considerably different metabolic profiles and dependencies in both primary AML patient samples and in AML cell lines. Although some cell lines expressed PDK1 in high amounts and had low oxygen consumption rates, others were predominantly driven by oxidative phosphorylation. PDK inhibition decreased leukemic cell growth and induced apoptosis, primarily in the cell lines that were more dependent on PDK1 metabolism. This same pattern was noted in a panel of AML patient samples. Further, inhibition of PDK1 sensitized AML cells to inhibition of glutaminolysis, and the authors noted this could be exploited clinically to metabolically rewire AML.

Disclosure: The authors reported no conflicts of interest.

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