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

1.AML1/EVI-1是一种嵌合转录因子，在慢性髓性白血病（CML）和骨髓增生异常综合征（MDS）的成母细胞转化中起致病作用。AML1/EVI-1通过被TGFI3信号激活的pai -1启动子抑制转录。AML1/ evi -1特异性结合TGFβ细胞内信号传感器Smad3，并抑制其功能。由于AMLI/EVI-1结合了一个辅助抑制因子CtBP，组蛋白去乙酰化酶的募集可能是一个潜在的机制。AML1/EVI-1也通过与CtBP的关联干扰AMIL -1介导的转录。此外，AML1/ evi - 1阻断G-CSF诱导的32D细胞分化，这取决于evi - 1部分的ctbp结合区域。这些数据表明，AMLI/ evi -1部分通过消除TGFβ信号和阻断AML1功能将CML或MIDS进展为急性白血病。我们使用诱导性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髓细胞发育。然而，AML 1缺陷骨髓显示巨核细胞成熟抑制，造血祖细胞增加，t淋巴细胞和b淋巴细胞发育缺陷。这些数据表明，AML1对于巨核细胞的成熟和T细胞和B细胞的分化是必需的，但对于成人造血干细胞的维持不是必需的。我们产生了MEN基因敲除小鼠。胚胎死亡，在E6.5前和着床后死亡。研究发现，在小鼠植入后发育过程中，MEN作为一种延伸因子发挥着非冗余的作用。

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.