Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome

• Published in: Blood 2003-10, Vol.102 (8), p.2960-2968
• Main Authors: Xu, Gang, Nagano, Masumi, Kanezaki, Rika, Toki, Tsutomu, Hayashi, Yasuhide, Taketani, Takeshi, Taki, Tomohiko, Mitui, Tetsuo, Koike, Kenichi, Kato, Koji, Imaizumi, Masue, Sekine, Isao, Ikeda, Yasuhiko, Hanada, Ryoji, Sako, Masahiro, Kudo, Kazuko, Kojima, Seiji, Ohneda, Osamu, Yamamoto, Masayuki, Ito, Etsuro
• Format: Article
• Language: English
• Subjects: Age Factors; Biological and medical sciences; Cell Differentiation; Cell Line; Cell Lineage; DNA, Complementary - metabolism; DNA-Binding Proteins - genetics; Down Syndrome - complications; Down Syndrome - genetics; Erythroid-Specific DNA-Binding Factors; Exons; Female; Flow Cytometry; GATA1 Transcription Factor; Genetic Vectors; Hematologic and hematopoietic diseases; Humans; Immunoblotting; Infant, Newborn; K562 Cells; Leukemia, Megakaryoblastic, Acute - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Models, Genetic; Mutation; Myeloproliferative Disorders - genetics; Protein Structure, Tertiary; Retroviridae - genetics; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; Transcription Factors - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-02-0390

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.