Identification of the causative genes fox Down syndrome associated acute megakaryocytic leukemia

我们进行了这项研究，以确定唐氏综合征中一过性骨髓增生性疾病（TMD）的致病基因。，得到如下结果：1。TMD候选致病基因分析。我们在此报告，在22例TMD患者中，有21例发现GATA-1基因n端区域对应的序列突变。我们最近遇到了患有TMD和DS的同卵双胞胎女性。两名患者都有相同的GATA-1基因突变。我们的研究结果提供了明确的证据，表明患有DS.2的AMKL患者在子宫内发生GATA1突变。染色体21q11.2 TMD候选基因的cDNA克隆。我们在21q11-21区域分离到了新的基因，这可能是TMD.3的候选位点。唐氏综合征相关AMKL （DS-AMKL）模型小鼠的生成。我们在GATA-1基因座造血调控域的控制下，获得了携带人BACH1 cDNA的转基因小鼠系。转基因小鼠系表现出明显的血小板减少，与巨核细胞核和细胞质成熟受损相关，并发生骨髓纤维化。我们将BACH1转基因小鼠与GATA-1敲除小鼠杂交，目前正在对这些小鼠进行分析。GATA-1突变致白血病的机制分析。为此，我们建立了表达全长GATA-1的DS-AMKL细胞系。此外，我们成功地通过RNAi技术敲除短形式GATA-1的表达。

We performed this study to identify the causative genes for transient myeloproliferative disorder (TMD) in Down syndrome., and found the following results.1.Analysis of the candidate of the causative genes for TMD.We report here that mutations in the sequences corresponding to the N-terminal region in the GATA-1 gene were found in 21 out of 22 cases with TMD. We recently encountered identical twin females who had TMD with DS. Both patients had an identical mutation in the GATA-1 gene. Our results provide definitive evidence that GATA1 mutations occur in utero in cases of AMKL with DS.2.cDNA cloning of the candidate genes for TMD on chromosome 21q11.2.We isolated novel genes in the region of 21q11-21, the possible candidate location for TMD.3.Generation of the model mouse for Down syndrome associated AMKL (DS-AMKL).We generated transgenic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The transgenic mouse lines showed significant thrombocytopenia associated with impaired nuclear and cytoplasmic maturation of the megakaryocytes, and developed myelofibrosis. We crossed the BACH1 transgenic mice with GATA-1 knock down mice, and we are now in the process of analyzing these mice.4.The analysis of the mechanisms of leukemogenesis by GATA-1 mutations.For this purpose, we established DS-AMKL cell line, which expressed full length GATA-1. Furthermore, we successfully knocked down the expression of short form of GATA-1 by RNAi techniques.