Abstract
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.
Highlights
Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity
As the presence of a physiological PE concentration in mitochondria membranes is reported to be critical for the oxidative phosphorylation pathway[10,11], we investigated mitochondria respiratory chain activity
Analyses done on target cells by using MitoTracker Red and Green to assess mitochondria potential and mass showed an absolute increase of mitochondrial mass (Fig. 1a; 1.38 and 1.33 fold increase in ETNK1-N244S and ETNK1-KO compared to ETNK1-WT; p = 0.0099 and p = 0.0254, respectively) and activity in both mutated and knock-out ETNK1 lines (Fig. 1b; 1.87 and 2.48 fold increase in ETNK1N244S and ETNK1-KO compared to ETNK1-WT; p = 0.0002 and p < 0.0001, respectively), suggesting an association between inhibition of ETNK1 activity and increased mitochondrial polarization and mass
Summary
Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. By using Generation Sequencing techniques, we and others identified recurrent missense somatic mutations occurring on ETNK1 in about 13% of patients affected by atypical chronic myeloid leukemia (aCML)[6], in 3–14% of chronic myelomonocytic leukemia (CMML)[6,7], and in 20% of systemic mastocytosis (SM) patients with eosinophilia[7]. Following these findings, ETNK1 mutations were included in the World Health Organization (WHO) 2016 classification as a support criterion for the diagnosis of aCML8. We show that treatment with P-Et is able to fully counteract this process
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