title: Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.
abstract: Transient myeloproliferative disorder (TMD) is a leukemoid reaction occurring occasionally in Down syndrome newborn infants. Acute megakaryocytic leukemia (AMKL) develops in approximately 20% to 30% of the cases with TMD. Recently, acquired mutations in the N-terminal activation domain of the GATA-1 gene, encoding the erythroid/megakaryocytic transcription factor GATA-1, have been reported in Down syndrome-related AMKL (DS-AMKL). To understand the multistep leukemogenesis in Down syndrome, GATA-1 mutations were investigated in patients with TMD. We show here that mutations in the GATA-1 gene were detected in 21 of 22 cases with TMD. Most of the mutations in TMD were located in the regions including exon 2 and were essentially identical to those observed in DS-AMKL. In the DS-AMKL cell line, MGS, which itself expresses only a truncated mutant of GATA-1, expression of full-length GATA-1 induced the differentiation toward the erythroid lineage. However, expression of the short form of GATA-1 did not induce erythroid differentiation. These results indicate that expression of GATA-1 with a defective N-terminal activation domain contributes to the expansion of TMD blast cells and that other genetic changes contribute to the development of AMKL in Down syndrome.
authors.affiliation: Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori, 036-8563 Japan.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Masumi
authors.initials: M
authors.lastname: Nagano
authors.forename: Rika
authors.initials: R
authors.lastname: Kanezaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Taketani
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Mitui
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koike
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.forename: Masue
authors.initials: M
authors.lastname: Imaizumi
authors.forename: Isao
authors.initials: I
authors.lastname: Sekine
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hanada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sako
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kudo
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
mesh_terms: D000367:Age Factors; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D050981:Erythroid-Specific DNA-Binding Factors; D005091:Exons; D005260:Female; D005434:Flow Cytometry; D050982:GATA1 Transcription Factor; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D020014:K562 Cells; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D014157:Transcription Factors