ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine

• Published in: Nature communications 2020-11, Vol.11 (1), p.5938-16, Article 5938
• Main Authors: Fontana, Diletta, Mauri, Mario, Renso, Rossella, Docci, Mattia, Crespiatico, Ilaria, Røst, Lisa M., Jang, Mi, Niro, Antonio, D’Aliberti, Deborah, Massimino, Luca, Bertagna, Mayla, Zambrotta, Giovanni, Bossi, Mario, Citterio, Stefania, Crescenzi, Barbara, Fanelli, Francesca, Cassina, Valeria, Corti, Roberta, Salerno, Domenico, Nardo, Luca, Chinello, Clizia, Mantegazza, Francesco, Mecucci, Cristina, Magni, Fulvio, Cavaletti, Guido, Bruheim, Per, Rea, Delphine, Larsen, Steen, Gambacorti-Passerini, Carlo, Piazza, Rocco
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 14/19; 14/28; 14/63; 38/77; 38/88; 38/91; 631/67/1990; 692/4017; 692/4028/67/1059; Cell Line; Cell Respiration - drug effects; Cell Respiration - genetics; DNA Breaks - drug effects; DNA damage; Electron Transport Complex II - drug effects; Electron Transport Complex II - metabolism; Enzymatic activity; Ethanolamine; Ethanolamines - metabolism; Ethanolamines - pharmacology; Histone H2A; Humanities and Social Sciences; Humans; Kinases; Leukemia; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; multidisciplinary; Mutation; Phenotype; Phenotypes; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Succinic Acid - metabolism; Supplements; Tigecycline - pharmacology; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19721-w

Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype. ETNK1 mutations are recurrent in leukemia but how they contribute to oncogenesis is still unclear. Here, the authors show that ETNK1 mutations increase mitochondrial activity, ROS and H2AX levels and that these effects can be rescued upon phosphoethanolamine supplementation.