Analysis of molecular mechanisms in leukemogenesis by chimeric transcription factors

AML 1/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）的母细胞转化中起着致病作用。AML 1/EVI-1通过派-1启动子抑制转录，而PAI-1启动子被TGFβ信号激活。AML 1/EVI-1特异性结合TGFβ Smad-3的胞内信号转导通路，抑制其功能。由于AML 1/EVI-1与辅阻遏物CtBP结合，组蛋白去乙酰化酶的募集可能是一种潜在机制。AML 1/EVI-1阻断G-CSF诱导的32 D细胞分化，这取决于EVI-1部分中的CtBP结合区域。提示AML 1/EVI-1可能通过阻断TGFβ信号通路而使CML或MDS向急性白血病发展。另一方面，EVI-1通过第一锌指结构域与JNK结合，并抑制其在包括UV在内的多种细胞应激刺激下的激酶活性。EVI-1依赖于第一锌指结构域保护3 T细胞免于凋亡。因此，AML 1/EVI-1通过阻断JNK介导的细胞凋亡可能是白血病发生发展的另一机制。MLL/MEN（也称为ELL）是在急性髓系白血病或MDS衍生性白血病中发现的一种白血病相关融合蛋白。由于MEN是一种RNA聚合酶因子，因此MLL/MEN也是一种嵌合转录因子。MEN和MLL/MEN均与p53结合，并通过p53结合位点抑制其转录能力。发现MEN通过N-末端部分与p53结合，并通过p53结合位点抑制其转录。MEN刺激Rat 1细胞在半固体琼脂中依赖于p53结合或抑制结构域的生长。MEN的过表达或异常表达可能在髓系白血病的发生发展中起重要作用。我们产生了MEN的敲除小鼠。胚胎致死，在E6.5前和着床后死亡。MEN应在小鼠着床后发育中作为延长因子发挥非冗余作用。

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-1 promoter that was activated by TGFβ signals. AML1/EVI-1 specifically bound to an intracellular signal transducer of TGFβ Smad-3, and inhibited its functions. Because AML1/EVI-1 bound to a corepressor CtBP, recruitment of histone deacetylase could be an underlying mechanism. AML1/EVI-1 blocked differentiation of 32D cells induced by G-CSF, depending on the CtBP-binding region in the EVI-1 portion. These data indicate that AML1/EVI-1 progresses CML or MDS to acute leukemia partly through abolishing TGFβ signals. On the other hand, EVI-1 bound to JNK through the 1st zinc finger domain and inhibited its kinase activities stimulated by several cellular stresses including UV. EVI-1 protected 3T cells from apoptosis depending on the 1st zinc finger domain. Therefore, blocking JNK-mediated apoptosis could be another mechanism in development of leukemia by AML1/EVI-1.MLL/MEN (also termed as ELL) is a leukemia-related fusion protein found in acute myeloid leukemia or MDS-derived leukemia. Because MEN is an RNA polymerase factor, MLL/MEN is also a chimeric transcription factor. Both MEN and MLL/MEN bound to p53 and repressed its transcriptional abilities through the p53-binding sites. MEN was found to bind to p53 through the N-terminal portion and inhibit its transcription through the p53-binding sites. MEN stimulated growth of Rat1 cells in a semi-solid agar depending of p53-binding or repressing domain. Overexpression or aberrant expression of MEN may play an important role in development of myeloid leukemia. We generated knockout mice of MEN. They were embryonic lethal, and die before E6.5 and after implantation. MEN should play a non-redundant role as an elongation factor in postimplantation development of mice.