title: Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia.
abstract: ETV6-related thrombocytopenia is an autosomal dominant thrombocytopenia that has been recently identified in a few families and has been suspected to predispose to hematologic malignancies. To gain further information on this disorder, we searched for ETV6 mutations in the 130 families with inherited thrombocytopenia of unknown origin from our cohort of 274 consecutive pedigrees with familial thrombocytopenia. We identified 20 patients with ETV6-related thrombocytopenia from seven pedigrees. They have five different ETV6 variants, including three novel mutations affecting the highly conserved E26 transformation-specific domain. The relative frequency of ETV6-related thrombocytopenia was 2.6% in the whole case series and 4.6% among the families with known forms of inherited thrombocytopenia. The degree of thrombocytopenia and bleeding tendency of the patients with ETV6-related thrombocytopenia were mild, but four subjects developed B-cell acute lymphoblastic leukemia during childhood, resulting in a significantly higher incidence of this condition compared to that in the general population. Clinical and laboratory findings did not identify any particular defects that could lead to the suspicion of this disorder from the routine diagnostic workup. However, at variance with most inherited thrombocytopenias, platelets were not enlarged. In vitro studies revealed that the maturation of the patients' megakaryocytes was defective and that the patients have impaired proplatelet formation. Moreover, platelets from patients with ETV6-related thrombocytopenia have reduced ability to spread on fibrinogen. Since the dominant thrombocytopenias due to mutations in RUNX1 and ANKRD26 are also characterized by normal platelet size and predispose to hematologic malignancies, we suggest that screening for ETV6, RUNX1 and ANKRD26 mutations should be performed in all subjects with autosomal dominant thrombocytopenia and normal platelet size.
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Melazzini
authors.affiliation: Department of Medical and Surgical Science, Policlinico Sant'Orsola Malpighi and University of Bologna, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Palombo
authors.affiliation: Department of Molecular Medicine, University of Pavia, Italy.|Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balduini
authors.affiliation: Department of Medical, Surgical and Health Sciences, IRCCS Burlo Garofolo and University of Trieste, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Rocco
authors.affiliation: Department of Medical and Surgical Science, Policlinico Sant'Orsola Malpighi and University of Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marconi
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
authors.affiliation: Department of Medical, Surgical and Health Sciences, IRCCS Burlo Garofolo and University of Trieste, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gnan
authors.affiliation: Department of Medical and Surgical Science, Policlinico Sant'Orsola Malpighi and University of Bologna, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bozzi
authors.affiliation: Department of Medical, Surgical and Health Sciences, IRCCS Burlo Garofolo and University of Trieste, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Faleschini
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Barozzi
authors.affiliation: University Hospital and Masaryk University, Brno, Czech Republic.
authors.forename: Michael
authors.initials: M
authors.lastname: Doubek
authors.affiliation: Department of Molecular Medicine, University of Pavia, Italy.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Di Buduo
authors.affiliation: Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Katerina Stano
authors.initials: KS
authors.lastname: Kozubik
authors.affiliation: Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Radova
authors.affiliation: Department of Oncology, Azienda "Santobono-Pausilipon", Pausilipon Hospital, Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Loffredo
authors.affiliation: Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: Maurice Wohl Institute, King's College London, UK.
authors.forename: Caterina
authors.initials: C
authors.lastname: Alfano
authors.affiliation: Department of Medical and Surgical Science, Policlinico Sant'Orsola Malpighi and University of Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy.
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy alessandro.pecci@unipv.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pecci
authors.affiliation: Department of Medical, Surgical and Health Sciences, IRCCS Burlo Garofolo and University of Trieste, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
mesh_terms: D000293:Adolescent; D000328:Adult; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005190:Family; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D013921:Thrombocytopenia / Q000235:genetics* / Q000473:pathology; D055815:Young Adult; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C583630:ANKRD26 protein, human; C493728:RUNX1 protein, human