@article{3001794,
    title = "Recurrent ETNK1 mutations in atypical chronic myeloid leukemia",
    author = "Gambacorti-Passerini, C.B. and Donadoni, C. and Parmiani, A. and Pirola, A. and Redaelli, S. and Signore, G. and Piazza, V. and Malcovati, L. and Fontana, D. and Spinelli, R. and Magistroni, V. and Gaipa, G. and Peronaci, M. and Morotti, A. and Panuzzo, C. and Saglio, G. and Usala, E. and Kim, D.-W. and Rea, D. and Zervakis, K. and Viniou, N. and Symeonidis, A. and Becker, H. and Boultwood, J. and Campiotti, L. and Carrabba, M. and Elli, E. and Bignell, G.R. and Papaemmanuil, E. and Campbell, P.J. and Cazzola, M. and Piazza, R.",
    journal = "Blood advances",
    year = "2015",
    volume = "125",
    number = "3",
    pages = "499-503",
    publisher = "American Society of Hematology",
    doi = "10.1182/blood-2014-06-579466",
    keywords = "ethanolamine kinase;  ethanolamine kinase 1;  phosphoethanolamine;  phosphorylcholine;  phosphotransferase;  unclassified drug;  ethanolamine kinase;  phosphotransferase, Article;  atypical chronic myeloid leukemia;  catalysis;  cell line;  chronic myelomonocytic leukemia;  clone;  controlled study;  dominant gene;  enzyme activity;  enzyme inhibition;  gene identification;  gene sequence;  genetic variability;  hematologic disease;  heterozygote;  human;  major clinical study;  missense mutation;  myelodysplastic syndrome;  myeloproliferative disorder;  nonsense mutation;  priority journal;  quantitative analysis;  somatic mutation;  tf1 cell;  amino acid sequence;  case control study;  chronic myeloid leukemia;  comparative study;  follow up;  genetics;  molecular genetics;  mutation;  prognosis;  sequence homology, Amino Acid Sequence;  Case-Control Studies;  Follow-Up Studies;  Humans;  Leukemia, Myelogenous, Chronic, BCR-ABL Positive;  Leukemia, Myelomonocytic, Chronic;  Molecular Sequence Data;  Mutation;  Phosphotransferases (Alcohol Group Acceptor);  Prognosis;  Sequence Homology, Amino Acid",
    abstract = "Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples ( P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders. © 2015 by The American Society of Hematology."
}