Molecular mechanism of hematopoietic regulation by leukemia-related transcription factor AML1(PEBP2αB)

白血病相关转录因子AML1(PEBP2αB)调节造血的分子机制

• 批准号: 10670961
• 负责人: OKUDA Tsukasa
• 金额: $ 2.11万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670961/
• 关键词: AML1; PEBP2; leukemia; hematopoiesis; transcription; embryonic stem(ES) cell; oncogene; gene targeting; 胚幹(ES)細胞

We analyzed the molecular mechanism of actions played by leukemia-related transcription factor, AML1(PEBP2αB), on hematopoietic regulation by using an in vitro experimental system, which was newly established through this research project. Our results are summarized as follows :1. We established an in vitro experimental system by using murine embryonic stem(ES) cell differentiation, through which the in vivo hematological phenotype observed in the AML1-deficient animals could be replicated in vitro.2. The hematopoietic defect resulting from homozygous null allele for AML1 could be rescued by re-expressing wild-type AML1 cDNA, indicating compelling evidence that the AML1-knockout phenotype is due solely to the lack of this gene.3. This rescue was observed in vivo in that the rescue clones contribute to lympho-hematopoiesis in chimera mice.4. The rescue required the transactivation domain of AML1 molecule.5. Forced expression of the same AML1 cDNA did not rescue the hematopoietic defect, suggesting that transcriptional control of AML1 was important for the biologic activity of the PEBP2 transcription complex. Consistent with this observation, the expression level of AML1 fluctuated as ES cells differentiated in vitro.6. We analyzed the expression of the known AML1-target genes and found that most of them were retained even in the absence of the active AML1 molecule. Therefore, it is suggested that as yet un-identified transcriptional target(s) exists which mediates AML1's biologic activities.

我们利用本研究项目新建立的体外实验系统分析了白血病相关转录因子AML1（PEBP2αB）对造血调节的分子机制。我们的研究结果总结如下： 1．建立了利用小鼠胚胎干（ES）细胞分化的体外实验系统，通过该系统可以在体外复制在AML1缺陷动物中观察到的体内血液学表型。2．由 AML1 纯合无效等位基因产生的 AML1 可以通过重新表达野生型 AML1 cDNA 来挽救，这表明有令人信服的证据表明 AML1 敲除表型完全是由于缺乏该基因所致。3。拯救克隆有助于嵌合体小鼠的淋巴造血。4．拯救需要AML1分子的反式激活结构域。5．强制表达相同的AML1 cDNA并不能拯救嵌合体小鼠的淋巴造血。造血缺陷，表明 AML1 的转录控制对于 PEBP2 转录复合物的生物活性很重要，与这一观察结果一致，随着 ES 细胞在体外分化，AML1 的表达水平发生波动。6。并发现即使在不存在活性 AML1 分子的情况下，它们中的大多数仍被保留。因此，表明存在尚未识别的介导转录靶标。 AML1的生物活性。

项目成果

Okuda,T.: "Role of AML1 in normal and leukemic hematopoiesis.In"Molecular Target for Hematological Malignancies and Cancer"(Ed.by Niho Y.)"Kyushu University Press(Fukuoka,Japan). (印刷中) (2000)

Okuda, T.：“AML1 在正常和白血病造血中的作用。见“血液恶性肿瘤和癌症的分子靶标”（Niho Y. 编）”九州大学出版社（福冈，日本）（印刷中）（2000 年）。

Iwai, T.: "Frequent aberration of FHIT gene expression in acute leukemias." Cancer Research. 58・22. 5182-5187 (1998)

Iwai, T.：“急性白血病中 FHIT 基因表达的频繁异常。”58・22（1998）。

Okuda T., Takeda K., Fujita Y. Nishimura M., Yagyu S., Yoshida M.,Akira S., Downing J.R. and Abe T.: "Biological characteristics of the leukemia-associated transcriptional factor AML1 disclosed by hematopoietic rescue of AML1-deficient embryonic stem cell

Okuda T.、Takeda K.、Fujita Y. Nishimura M.、Yagyu S.、Yoshida M.、Akira S.、Downing J.R. 和 Abe T.：“造血拯救揭示的白血病相关转录因子 AML1 的生物学特征

Okuda T., Fujita Y., Nishimura M., Downing J.R., and Abe T.: "Role of AML1 in normal and leukemic hematopoiesis. In "Molecular Target for Hematological Malignancies and Cancer" (ed.by Niho Y.)"Kyushu University Press (Fukuoka,Japan). in press. (2000)

Okuda T.、Fujita Y.、Nishimura M.、Downing J.R. 和 Abe T.：“AML1 在正常和白血病造血中的作用。在“血液恶性肿瘤和癌症的分子靶点”（Niho Y. 编）中”九州

奥田司: "AML1遺伝子の生物学的意義"現代医療. 31・5. 1125-1134 (1999)

奥田司：“AML1 基因的生物学意义”现代医学 31・5（1999）。