Platelet GPIb: sensing force and responding

growth factor b inhibitors as a therapeutic option.In 2013, and after all these descriptions, Gotlib et al 8 tried to recapitulate the different genotypes that an aCML sample could present in comparison with chronic neutrophilic leukemia, which gave us an overview of the disease's complexity.These mutations are not mutually exclusive; for example, concomitant mutations of CSF3R and SETBP1 could be found in 14% of the patients.However, a complete description of the somatic mutations involved in the onset of aCML was still lacking.Using a whole-exome analysis approach on 15 aCML cases, and after their own description of SETBP1 mutation in aCML, 5 Gambacorti-Passerini et al described 2 point mutations of an ethanolamine kinase called ETNK1, an enzyme that is physiologically involved in the first step of the phosphatidylethanolamine biosynthesis pathway.In a large cohort of 515 hematologic clonal disorders, the authors described recurrent ETNK1 heterozygous mutations in 9% of atypical CML and 3% of CMML samples.The described mutations are all restricted in the kinase domain, affecting 2 hot spot codons (H243Y and mainly N244S), as shown in the figure.The authors also showed that these mutations are associated with impaired catalytic activity of the kinase, leading to an important decrease in the intracellular phosphoethanolamine/phosphocholine ratio.These results, obtained on patient samples, were confirmed on TF1 cell lines transduced with wild-type or mutated ETNK1, suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme.ETNK1 is responsible for the phosphorylation of ethanolamine to phosphoethanolamine, which is involved in many biochemical processes, mainly in the definition of the membrane architecture and participating in the respiratory complexes in the inner membrane of mitochondria.Given the pleiotropic role of phosphoethanolamine, the evaluation of biological effects of the ETNK1 mutations will be a challenging task.All these studies clearly showed that aCML and CMML share not only clinical and morphologic features but also mutant genes, especially CSF3R, SETBP1 and ETNK1,