Highlights from

ASH 2020

62nd Annual Meeting & Exposition of the American Society of Hematology

Virtual 5 - 8 December 2020

New mechanism in atypical CML detected and tackled

Atypical chronic myeloid leukaemia (aCML) is a clonal disorder belonging to the myelodysplastic/myeloproliferative neoplasm syndromes. Recent findings suggest a new mechanism by which the reduced activity of mutated ETNK1 kinase leads to the accumulation of new DNA damage.

ETNK1 kinase is responsible for the phosphorylation of ethanolamine to phosphoethanolamine (P-Et). Recurrent somatic mutations in the ETNK1 gene were identified in about 13% of patients affected by aCML; 3-14% of patients affected by chronic myelomonocytic leukaemia (CMML); and 20% of patients affected by systemic mastocytosis with eosinophilia. ETNK1 mutations cluster in a very narrow region of the catalytic domain of this enzyme and cause an impairment of the enzymatic activity of ETNK1, leading to a significant decrease in the intracellular concentration of P-Et. Despite this evidence, the oncogenic role of these mutations remained largely unexplained.

Dr Diletta Fontana (University of Milano-Bicocca, Italy) investigated the specific role of ETNK1 mutations by using cellular CRISPR/Cas9 and ETNK1 overexpression models as well as samples from aCML patients. Results showed that mutated ETNK1 causes a significant increase in mitochondrial activity (P=0.0002) and in production of reactive oxygen species (ROS, P<0.0001), known to cause DNA oxidative damage. The investigators hypothesised that the decreased P-Et concentration in ETNK1-mutated cells could be responsible for these observations. When treated with P-Et, a cell line containing the ETNK1-N244S mutation showed a complete restoration of the normal mitochondrial membrane potential and generation of ROS. Moreover, the mutator phenotype was reverted by P-Et treatment. These findings support the hypothesis that lack of P-Et is directly involved in the induction of DNA damage. In vivo studies are required to address the therapeutic potential of P-Et.

  1. Fontana D, et al. ETNK1 Mutations in Atypical Chronic Myeloid Leukemia Induce a Mutator Phenotype That Can be Reverted with Phosphoethanolamine. 62nd ASH Annual Meeting, December 5-8, 2020. Abstract LBA-5.

Top image: @ iStockPhoto: ustas7777777

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.