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

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.

Regulation of Membrane Phospholipid Homeostasis in Neurodegenerative Diseases

“…Specifically, reduced mitochondrial PE synthesis from PS had led to decreased level of mitochondrial respiration, along with disrupted IMM morphology and CL loss in muscle cells, despite the rescue efforts with the up-regulation of Parkin [103]. Furthermore, phosphoethanolamine (PEA), a substrate for PE synthesis, had been shown to disrupt mitochondrial respiration by indirect inhibition of the ETC protein complexes [104], more specifically by the inhibition of complex II [105].…”

Molecular Pathogenesis of BCR-ABL-Negative Atypical Chronic Myeloid Leukemia

“…Mutations clustering in the same hotspot of the kinase catalytic domain (N244S, N244T, N244K, G245A, G245V) were subsequently found also in 0%–14% of CMML cases ( 23 , 94 ), in 20% of patients affected by aggressive systemic mastocytosis (SM) with eosinophilia ( 94 ), and in a single case of diffuse large B-cell lymphoma (DLBCL) ( 95 ). Recently, our group demonstrated that somatic ETNK1 mutations are responsible for a reduced activity of the enzyme, causing a decrease in P-Et synthesis ( 23 , 96 ). Through the reduced competition of P-Et with succinate at mitochondrial complex II, an increased mitochondrial hyperactivation is triggered, which in turn is responsible for increased ROS production and subsequent DNA damage and accumulation of further mutations ( 96 ).…”

“…Recently, our group demonstrated that somatic ETNK1 mutations are responsible for a reduced activity of the enzyme, causing a decrease in P-Et synthesis ( 23 , 96 ). Through the reduced competition of P-Et with succinate at mitochondrial complex II, an increased mitochondrial hyperactivation is triggered, which in turn is responsible for increased ROS production and subsequent DNA damage and accumulation of further mutations ( 96 ). Treatment with exogenous P-Et is able to restore a normal phenotype, protecting cells from ROS-mediated DNA damage ( 96 , 97 ) ( Figure 2 ).…”

“…Through the reduced competition of P-Et with succinate at mitochondrial complex II, an increased mitochondrial hyperactivation is triggered, which in turn is responsible for increased ROS production and subsequent DNA damage and accumulation of further mutations ( 96 ). Treatment with exogenous P-Et is able to restore a normal phenotype, protecting cells from ROS-mediated DNA damage ( 96 , 97 ) ( Figure 2 ). Notably, recent findings suggest that, whenever present, ETNK1 mutations occur at the initial stages of the clonal evolution of aCML ( 14 ), preceding other driver events, such as ASXL1 or SETBP1 , which indirectly supports the role of ETNK1 as an inducer of a mutator phenotype.…”

Atypical Chronic Myelogenous Leukemia, BCR-ABL1 Negative: Diagnostic Criteria and Treatment Approaches

“…Although the presence of ETNK1 mutations has been considered as a relatively specific finding for aCML, leading to their inclusion in the 2016 WHO classification as a support criterion for the diagnosis of the disease, they have also been found in chronic myelomonocytic leukemia (CMML) and systemic mastocytosis with eosinophilia ( 34 ) while they were recently described in diffuse large B-cell lymphoma ( 35 ). Nevertheless, the interest in ETNK1 mutations remains high due to the fact that phosphoethanolamine, the metabolic product of ETNK1, has been shown to negatively control mitochondrial activity, thus restoring a normal phenotype ( 24 ).…”