They discover a new metabolic profile in patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is a pathology with high genetic, clinical and metabolic heterogeneity, which hinders the success of currently available therapeutic treatments. Specifically, internal tandem duplications of the FLT3 gene (FLT3-ITD+) are the most prevalent mutations in AML patients and are associated with high relapse rates.

A recent study describes a specific metabolic adaptation in some acute myeloid leukemia patients affected by tandem mutations in the FLT3 gene. The discovery, which could open up new options for future combined therapies of a specific nature for this type of patient, is the result of collaboration between the teams led by Professor Marta Cascante, from the Faculty of Biology, the Institute of Biomedicine of the University of Barcelona (IBUB) and the CIBER of Liver and Digestive Diseases (CIBEREHD), in Spain, as well as Professor Jan Jacob Schuringa, from the University of Groningen (The Netherlands).

With the participation of professor Silvia Marín (UB-IBUB), the work has as its first author the researcher Ayşegül Erdem, who has just received her doctorate under the supervision of Cascante and Schuringa within the framework of the European project «Deciphering the metabolism of haematological cancers » (HaemMetabolome).

The new work defines a new specific metabolic profile related to patients with the FLT3-ITD+ phenotype. To achieve the results, the team has applied innovative metabolomics, proteomics and tracer-based metabolomics (SIRM) techniques. Thus, they have discovered that the leukemic cells of patients with these mutations present elevated levels of the enzymes succinate-CoA ligases and a high activity of complex II of the mitochondrial electronic transport chain that provides energy for cellular metabolism.

In addition, the study demonstrates for the first time that this subtype of leukemic cells uses lactate as a substrate for mitochondrial respiration. “For this reason, this profile of tumor cells could be very sensitive to the simultaneous pharmacological inhibition of complex II of the respiratory chain and of the lactate transporter”, explains Professor Marta Cascante, from the Department of Biochemistry and Molecular Biomedicine of the UB.

Research group led by Professor Marta Cascante. (Photo: University of Barcelona. CC BY)

In all cells, the main substrates of the mitochondrial respiration chain are pyruvate (from glucose) or other carbohydrates or amino acids that give rise to pyruvate, in addition to ketone bodies, glutamine, and fatty acids. “However, in general, lactate had not been described until now as a substrate for mitochondrial respiration in tumor cells”, adds Cascante.

As the study reveals, the mitochondrial respiration chain in these leukemia cells could be pharmacologically inhibited if complex II inhibitors (specifically, TTFA and 3-NPA compounds) were synergistically combined with those of the lactate transporter MCT1 (CHC and AZD3965).

In addition, the results of the study help to better understand the metabolic profile of the leukemic cells of each patient, which could open up new and potential possibilities in the design of specific combined therapies, based on the specific genetic mutations that are identified in a person. “Personalized medicine, which aims to establish specific therapies for each patient according to the phenotype of their tumor, implies having the best knowledge of each patient’s tumor in order to be able to offer them the best therapeutic option for their particular case”, concludes the researcher Martha Cascante.

The study is titled “Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fueled respiratory metabolic vulnerability.” And it has been published in the academic journal Nature Communications. (Source: UB)