title: Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21.
abstract: Patients with Down syndrome (DS) frequently develop 2 kinds of clonal megakaryocytosis: a common, congenital, spontaneously resolving, transient myeloproliferative disorder (TMD) and, less commonly, childhood acute megakaryoblastic leukemia (AMKL). Recently, acquired mutations in exon 2 of GATA1, an X-linked gene encoding a transcription factor that promotes megakaryocytic differentiation, were described in 6 DS patients with AMKL. The mutations prevent the synthesis of the full-length GATA1, but allow the synthesis of a shorter GATA1 protein (GATA1s) that lacks the transactivation domain. To test whether mutated GATA1 is involved in the initiation of clonal megakaryoblastic proliferation or in the progression to AMKL, we screened 35 DS patients with either AMKL or TMD and 7 non-DS children with AMKL for mutations in exon 2 of GATA1. Mutations were identified in 16 of 18 DS patients with AMKL, in 16 of 17 DS patients with TMD, and in 2 identical twins with AMKL and acquired trisomy 21. Analysis revealed various types of mutations in GATA1, including deletion/insertions, splice mutations, and nonsense and missense point mutations, all of which prevent the generation of full-length GATA1, but preserve the translation of GATA1s. We also show that the likely mechanism of generation of GATA1 isoforms is alternative splicing of exon 2 rather than, or in addition to, alternative translation initiation, as was proposed before. These findings suggest that acquired intrauterine inactivating mutations in GATA1 and generation of GATA1s cooperate frequently with trisomy 21 in initiating megakaryoblastic proliferation, but are insufficient for progression to AMKL.
authors.affiliation: Department of Pediatric Hemato-Oncology, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel 52621.
authors.forename: Liat
authors.initials: L
authors.lastname: Rainis
authors.forename: Dan
authors.initials: D
authors.lastname: Bercovich
authors.forename: Sabine
authors.initials: S
authors.lastname: Strehl
authors.forename: Andrea
authors.initials: A
authors.lastname: Teigler-Schlegel
authors.forename: Batia
authors.initials: B
authors.lastname: Stark
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Inna
authors.initials: I
authors.lastname: Muler
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Helena
authors.initials: H
authors.lastname: Kempski
authors.forename: Oskar A
authors.initials: OA
authors.lastname: Haas
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
mesh_terms: D017398:Alternative Splicing; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D050981:Erythroid-Specific DNA-Binding Factors; D005091:Exons / Q000235:genetics*; D005260:Female; D050982:GATA1 Transcription Factor; D006801:Humans; D007223:Infant; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology / Q000235:genetics*; D008297:Male; D008533:Megakaryocytes / Q000473:pathology; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics*; D020033:Protein Isoforms; D014157:Transcription Factors / Q000235:genetics*; D014314:Trisomy
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D020033:Protein Isoforms; D014157:Transcription Factors