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Development of new immune cell therapies with human leukemia model mouse.

利用人类白血病模型小鼠开发新的免疫细胞疗法。

基本信息

批准号：
12557078
负责人：
MITANI Kinuko
金额：
$ 7.49万
依托单位：
Dokkyo University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

1.AML1/EVI-1 is a chimeric transcription factor that plays a causative role in blastic transformation of chronic myelogenous leukemia (CML) and myelodysplastic syndrome (MDS). AML1/EVI-1 repressed transcription through PAI-1promoter that was activated by TGFI3 signals. AML1/EVI-1specifically bound to an intracellular signal transducer of TGFβ, Smad3, and inhibited its functions. Because AMLI/EVI-1 bound to a corepressor CtBP, recruitment of histone deacetylase could be an underlying mechanism. AML1/EVI-1 also interfered with AMIL 1-mediated transcription through association with CtBP. Moreover, AML1/EVI-l blocked differentiation of 32D cells induced by G-CSF, depending on the CtBP-binding region in EVI-l portion. These data indicate that AMLI/EVI-1progresses CML or MIDS to acute leukemia partly through abolishing TGFβ signals and blocking AML1 functions.2.We assessed the requirement of AML 1 in adult hematopoiesis using an inducible gene-targeting method. In the absence of AML 1, hematopoietic progenitors were fully maintained with normal myeloid development. However, AML 1-deficient bone marrow showed inhibition of megakaryocytic maturation, increased hematopoietic progenitor cells and defective T-and B-lymphocyte development. These data indicate that AML1 is required for maturation of megakaryocytes and differentiation of T and B cells, but not for maintenance of hematopoietic stem cells in adult hematopoiesis.3.We generated knock-out mice of MEN. They were embryonic lethal, and die before E6.5 and after implantation. MEN was found to play a non-redundant role as an elongation factor in postimplantation development of mice.

1.AML1/EVI-1是一种嵌合转录因子，在慢性粒细胞白血病（CML）和骨髓增生异常综合征（MDS）的原始细胞转化中发挥致病作用。 AML1/EVI-1 通过由 TGFI3 信号激活的 PAI-1 启动子抑制转录。 AML1/EVI-1特异性结合细胞内信号转导因子TGFβ、Smad3，并抑制其功能。由于 AMLI/EVI-1 与辅阻遏物 CtBP 结合，组蛋白脱乙酰酶的募集可能是潜在机制。 AML1/EVI-1 还通过与 CtBP 结合干扰 AMIL 1 介导的转录。此外，AML1/EVI-1阻断由G-CSF诱导的32D细胞的分化，这取决于EVI-1部分中的CtBP结合区。这些数据表明AMLI/EVI-1部分通过消除TGFβ信号和阻断AML1功能而使CML或MIDS进展为急性白血病。2.我们使用诱导基因靶向方法评估了成人造血中AML 1的需求。在没有 AML 1 的情况下，造血祖细胞完全维持正常的骨髓发育。然而，AML 1 缺陷的骨髓表现出巨核细胞成熟受到抑制、造血祖细胞增加以及 T 淋巴细胞和 B 淋巴细胞发育缺陷。这些数据表明AML1是巨核细胞的成熟以及T细胞和B细胞的分化所必需的，但不是成人造血过程中造血干细胞维持所必需的。3.我们产生了MEN的基因敲除小鼠。它们是胚胎致死的，在 E6.5 之前和植入后死亡。研究发现，MEN 作为伸长因子在小鼠植入后发育中发挥着非冗余的作用。