title: Recurrent ETNK1 mutations in atypical chronic myeloid leukemia.
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.
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy; Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy;
authors.forename: Carlo B
authors.initials: CB
authors.lastname: Gambacorti-Passerini
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Carla
authors.initials: C
authors.lastname: Donadoni
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Parmiani
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pirola
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Redaelli
authors.affiliation: Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Signore
authors.affiliation: Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Piazza
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di ricovero e cura a carattere scientifico Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Diletta
authors.initials: D
authors.lastname: Fontana
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Spinelli
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Vera
authors.initials: V
authors.lastname: Magistroni
authors.affiliation: Tettamanti Research Center, Pediatric Clinic University of Milano-Bicocca, Monza, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gaipa
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Peronaci
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morotti
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy;
authors.forename: Cristina
authors.initials: C
authors.lastname: Panuzzo
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.affiliation: S.C. di Ematologia e Centro Trapianti di Cellule Staminali Emopoietiche, Dipartimento di Oncologia Medica, Ospedale Oncologico "Armando Businco," Cagliari, Italy;
authors.forename: Emilio
authors.initials: E
authors.lastname: Usala
authors.affiliation: Department of Hematology, Catholic University, Seoul, Korea;
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Service d'Hématologie adulte, Hôpital Saint-Louis, Paris, France;
authors.forename: Delphine
authors.initials: D
authors.lastname: Rea
authors.affiliation: 1st Department of Internal Medicine, Hematology Unit, LAIKON Hospital, National and Kapodistrian University of Athens, Athens, Greece;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Zervakis
authors.affiliation: 1st Department of Internal Medicine, Hematology Unit, LAIKON Hospital, National and Kapodistrian University of Athens, Athens, Greece;
authors.forename: Nora
authors.initials: N
authors.lastname: Viniou
authors.affiliation: Hematology Division, Department of Internal Medicine, University of Patras Medical School, Patras, Greece;
authors.forename: Argiris
authors.initials: A
authors.lastname: Symeonidis
authors.affiliation: Universitätsklinikum Freiburg, Innere Medizin I-Hämatologie, Onkologie, und Stammzelltransplantation, Freiburg, Germany;
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.affiliation: Leukaemia and Lymphoma Research Molecular Hematology Unit, John Radcliffe Hospital, Oxford, United Kingdom;
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Dipartimento Medicina Clinica e Sperimentale, Università Insubria, Varese, Italy;
authors.forename: Leonardo
authors.initials: L
authors.lastname: Campiotti
authors.affiliation: Ematologia e Trapianto di Midollo, Istituto di ricovero e cura a carattere scientifico, Ospedale San Raffaele, Milano, Italy;
authors.forename: Matteo
authors.initials: M
authors.lastname: Carrabba
authors.affiliation: Hematology Unit, San Gerardo Hospital, Monza, Italy; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Elli
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di ricovero e cura a carattere scientifico Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Rocco
authors.initials: R
authors.lastname: Piazza
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D005500:Follow-Up Studies; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011379:Prognosis; D017386:Sequence Homology, Amino Acid
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C020125:ethanolamine kinase