Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.
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.
Xu
Gang
G
Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori, 036-8563 Japan.
Nagano
Masumi
M
Kanezaki
Rika
R
Toki
Tsutomu
T
Hayashi
Yasuhide
Y
Taketani
Takeshi
T
Taki
Tomohiko
T
Mitui
Tetsuo
T
Koike
Kenichi
K
Kato
Koji
K
Imaizumi
Masue
M
Sekine
Isao
I
Ikeda
Yasuhiko
Y
Hanada
Ryoji
R
Sako
Masahiro
M
Kudo
Kazuko
K
Kojima
Seiji
S
Ohneda
Osamu
O
Yamamoto
Masayuki
M
Ito
Etsuro
E
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*
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D014157:Transcription Factors