04 May 2022

Scientists have discovered a marker of different metabolic states in patients with acute myeloid leukaemia (AML), revealing vulnerabilities which could be targeted with treatments.

AML develops due to a series of genetic abnormalities in hematopoietic stem cells. These abnormalities are often patient-specific, leading to various changes in cell characteristics.

A team made up of researchers from The Netherlands, Spain, and Brazil, looked at metabolic differences between AML cells and healthy haematopoietic stem and progenitor cells. They identified that an enzyme called Pyruvate dehydrogenase kinase 1, or PDK1, was on average overproduced in AML cells compared to normal blood stem cells.  

In lab tests, the team found that metabolically distinct subtypes of AML can be identified by expression levels of the enzyme PDK1.

"We show that human leukaemias display distinct metabolic states and adaptation mechanisms," they write in Nature Communications.

Some AML cells had higher levels of PDK1 and were more dependent on a mechanism called glycolysis to produce energy. Inhibition of PDK1 with a drug slowed the growth of AML cells from patients both in the lab and in mice.

Others with lower levels of PDK1 were dependent on oxidative phosphorylation, and in turn dependent on an amino acid called glutamine to provide the raw materials to produce energy. Blocking both PDK1 and Glutaminase (an enzyme which breaks down glutamine as the first step to energy production) killed AML cells and led to longer survival in mice.

“Insight into such differences will further aid our molecular and cell biological understanding of clonal heterogeneity in acute myeloid leukaemia and will also provide means for personalised and subclone-specific targeting strategies,” says Prof Marta Cascante of University of Barcelona, Spain, who led the research jointly with Professor Jan Jacob Schuringa, from the University of Groningen in the Netherlands.

Professor Cascante said: “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.”

Source: Erdem A, Marin S, Pereira-Martins DA, Cortés R, Cunningham A, Pruis MG, de Boer B, van den Heuvel FAJ, Geugien M, Wierenga ATJ, Brouwers-Vos AZ, Rego EM, Huls G, Cascante M, Schuringa JJ.  (2022) “The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia.” Nature Communications, doi: 10.1038/s41467-022-28737-3

Link: https://www.nature.com/articles/s41467-022-28737-3

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