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

福克斯唐氏综合症相关急性巨核细胞白血病致病基因的鉴定

• 批准号: 14370238
• 负责人: ITO Etsuro
• 金额: $ 8.83万
• 依托单位: Hirosaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370238/
• 关键词: GATA1; Bach1; Down syndrome; Acute megakaryocytic leukemia; TMD; transcriptional factor; transgenic mouse; GATA-1; TAM

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.

我们进行了这项研究，以确定唐氏综合征中短暂性骨髓增生性疾病（TMD）的致病基因。结果发现：1. TMD致病基因的候选基因分析：在22例TMD患者中，21例患者的加塔-1基因N端序列发生突变。我们最近遇到了同卵双胞胎女性谁有TMD与DS。两名患者的加塔-1基因突变相同。我们的研究结果为AMKL合并DS的病例在子宫内发生GATA 1突变提供了明确的证据。2.在染色体21 q11上进行TMD候选基因的cDNA克隆。2.在21 q11 -21区域分离到新基因，3.唐氏综合征相关AMKL（DS-AMKL）模型小鼠的建立我们产生了在加塔-1基因座造血调控结构域控制下携带人BACH 1 cDNA的转基因小鼠系。转基因小鼠系表现出与巨核细胞核和细胞质成熟受损相关的显著血小板减少症，并发生骨髓纤维化。我们将BACH 1转基因小鼠与加塔-1敲除小鼠杂交，目前正在对这些小鼠进行分析。4. GATA-1突变致白血病机制的分析为此，我们建立了表达全长加塔-1的DS-AMKL细胞系。此外，我们成功地敲低表达的短形式的加塔-1的RNAi技术。

项目成果

Xu G, Toki T, Ito E et al.: "Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down's syndrome"Blood. 102・8. 2960-2968 (2003)

Xu G、Toki T、Ito E 等：“唐氏综合征短暂性骨髓增生性疾病中 GATA-1 基因的频繁突变”Blood.102·8（2003）。

Shimada A, Toki T, Ito E et al.: "Fetal origin of the GATA-1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down's syndrome"Blood. 103・1. 366-366 (2004)

Shimada A、Toki T、Ito E 等：“患有短暂性骨髓增生性疾病和伴有唐氏综合症的急性巨核细胞白血病的同卵双胞胎中 GATA-1 突变的胎儿起源”Blood.366-366。

Kamio T, Toki T, Terui K, Ito E et al.: "The B cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs"Blood. 102・9. 3317-3322 (2003)

Kamio T、Toki T、Terui K、Ito E 等：“B 细胞特异性转录因子 BACH2 改变抗癌药物的细胞毒性作用”Blood.102·9。

The B cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs.

B 细胞特异性转录因子 BACH2 可以改变抗癌药物的细胞毒性作用。

• 发表时间: 2003
• 期刊: Blood 102
• 作者: Kamio T;Toki T;Terui K;Ito E et al.
• 通讯作者: Ito E et al.

Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment.

• DOI: 10.1182/blood-2004-07-2826
• 发表时间: 2005-04
• 期刊: Blood
• 影响因子: 20.3
• 作者: T. Toki;F. Katsuoka;Rika Kanezaki;Gang Xu;H. Kurotaki;Jiying Sun;T. Kamio;Seiji Watanabe;S. Tandai;K. Terui;S. Yagihashi;N. Komatsu;K. Igarashi;Masayuki Yamamoto;E. Ito