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 patients with acute myeloid leukemia affected by tandem mutations of 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 teams led by Professor Marta Cascante, from the Faculty of Biology, the Institute of Biomedicine from the University of Barcelona (IBUB) and the CIBER of Hepatic and Digestive Diseases (CIBEREHD), in Spain, as well as Professor Jan Jacob Schuringa, from the University of Groningen (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 hematological cancers” (HaemMetabolome).
The new work defines a new specific metabolic profile linked to patients with the FLT3-ITD+ phenotype. To achieve these results, the team applied innovative metabolomics, proteomics and tracer-based metabolomics (SIRM) techniques. Thus, they discovered that the leukemic cells of patients carrying these mutations present elevated levels of the enzymes succinate-CoA ligases and an elevated activity of complex II of the mitochondrial electronic transport chain which 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 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 PER)
In all cells, the main substrates of the mitochondrial respiratory chain are pyruvate (derived 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 leukemic 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 study results help to better understand the metabolic profile of each patient’s leukemic cells, which could open up potential new possibilities in the design of specific combination therapies, based on the specific genetic mutations identified in a person. . “Personalized medicine, which aims to establish specific therapies for each patient according to the phenotype of their tumor, involves 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 succinyl dehydrogenase complex in acute myeloid leukemia leads to lactate-fueled respiratory metabolic vulnerability.” And it was published in the academic journal Nature Communications. (Source: UB)