Analysis of molecular mechanisms in leukemogenesis by chimeric transcription factors

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)的急变过程中起重要作用。AML1/EVI-1通过转化生长因子β信号激活的PAI-1启动子抑制转录。AML1/EVI-1与转化生长因子βSmad-3的胞内信号转导通路特异性结合，并抑制其功能。由于AML1/EVI-1与辅阻遏子CtBP结合，组蛋白脱乙酰酶的募集可能是一个潜在的机制。AML1/EVI-1阻断G-CSF诱导的32D细胞分化，依赖于EVI-1部分的CtBP结合区。这些数据表明AML1/EVI-1通过部分阻断转化生长因子β信号使慢性粒细胞白血病或骨髓增生异常综合征进展为急性白血病。另一方面，EVI-1通过第一锌指结构域与JNK结合，并抑制包括紫外线在内的几种细胞应激刺激下的JNK的激酶活性。EVI-1对3T细胞的保护作用依赖于第一锌指结构域。因此，阻断JNK介导的细胞凋亡可能是AML1/EVI-1导致白血病发生的另一机制。MLL/MEN(又称ELL)是一种与白血病相关的融合蛋白，存在于急性髓系白血病或MDS来源的白血病中。由于MENS是一种RNA聚合因子，MLL/MENS也是一种嵌合转录因子。MAN和MLL/MEN都与P53结合，并通过P53结合位点抑制其转录能力。研究发现，MAN通过N端部分与P53结合，并通过P53结合位点抑制其转录。MENS刺激Rat1细胞在半固体琼脂中的生长依赖于P53结合或抑制结构域。男性的过度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。我们产生了人类的基因敲除老鼠。它们是胚胎致死的，在E6.5之前和植入后死亡。在小鼠的移植后发育中，男性应该扮演一个非多余的角色，作为一个延伸因素。

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.