Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome
Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome
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DOI：
10.1182/blood-2003-02-0390
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发表时间：
2003-10-15
期刊：
影响因子：
20.3
通讯作者：
Ito, E
中科院分区：
文献类型：
--
作者：
Xu, G;Nagano, M;Ito, E
短暂性骨髓增生性疾病（TMD）是一种类白血病反应，偶尔发生在唐氏综合征新生儿。急性巨核细胞白血病（AMKL）的发展约20%至30%的案件与TMD。最近，在唐氏综合征相关AMKL（DS-AMKL）中报告了编码红细胞/巨核细胞转录因子加塔-1的加塔-1基因的N-末端激活结构域的获得性突变。为了了解唐氏综合征中白血病发生的多步过程，我们对TMD患者的加塔-1基因突变进行了研究。我们在这里发现，22例TMD患者中有21例检测到了加塔-1基因突变。TMD中的大多数突变位于包括外显子2的区域，并且与在DS-AMKL中观察到的突变基本相同。在DS-AMKL细胞系MGS中，其本身仅表达加塔-1的截短突变体，全长加塔-1的表达诱导向红系分化。然而，短形式的加塔-1的表达不诱导红系分化。这些结果表明，具有缺陷的N-末端激活结构域的加塔-1的表达有助于TMD母细胞的扩增，并且其他遗传变化有助于唐氏综合征中AMKL的发展。（血。2003; 102：2960-2968）（C）2003年由美国血液学会。
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. (Blood. 2003; 102:2960-2968) (C) 2003 by The American Society of Hematology.