TY - JOUR
T1 - Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia
AU - Melazzini, Federica
AU - Palombo, Flavia
AU - Balduini, Alessandra
AU - De Rocco, Daniela
AU - Marconi, Caterina
AU - Noris, Patrizia
AU - Gnan, Chiara
AU - Pippucci, Tommaso
AU - Bozzi, Valeria
AU - Faleschini, Michela
AU - Barozzi, Serena
AU - Doubek, Michael
AU - Buduo, Christian A Di
AU - Kozubik, Katerina Stano
AU - Radova, Lenka
AU - Loffredo, Giuseppe
AU - Pospisilova, Sarka
AU - Alfano, Caterina
AU - Seri, Marco
AU - Balduini, Carlo L.
AU - Pecci, Alessandro
AU - Savoia, Anna
PY - 2016/10/31
Y1 - 2016/10/31
N2 - 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 transformationspecific 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 ANKRD26mutations should be performed in all subjects with autosomal dominant thrombocytopenia and normal platelet size.
AB - 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 transformationspecific 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 ANKRD26mutations should be performed in all subjects with autosomal dominant thrombocytopenia and normal platelet size.
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U2 - 10.3324/haematol.2016.147496
DO - 10.3324/haematol.2016.147496
M3 - Article
AN - SCOPUS:84994654361
VL - 101
SP - 1333
EP - 1342
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 11
ER -