Molecular mechanisms of leukemogenesis by AML1/EVI-1
Molecular mechanisms of leukemogenesis by AML1/EVI-1
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DOI：
10.1038/sj.onc.1207777
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发表时间：
2004-05-24
期刊：
影响因子：
8
通讯作者：
Mitani, K
中科院分区：
文献类型：
--
作者：
Mitani, K
AML1/EVI-1嵌合基因由t(3;21)(q26;q22)易位产生，在慢性粒细胞白血病和骨髓增生异常综合征等造血干细胞恶性肿瘤的进展中发挥关键作用。在 AML1/EVI-1 中，包含矮同源结构域的 AML1 N 末端一半与整个锌指 EVI-1 蛋白融合。 AML1 对于胎儿肝脏中的造血细胞发育及其在成人中的谱系特异性分化至关重要。相比之下，EVI-1在正常造血细胞中几乎不表达，但在急变期的慢性粒细胞白血病和骨髓增生异常综合征衍生的白血病中过度表达。 AML1/EVI-1融合蛋白中至少确定了四种可能导致造血干细胞恶性转化的机制。首先，AML1/EVI-1 对 AML1 诱导的转录激活发挥显性负效应。尽管 AML1/EVI-1 抑制的靶基因仍不清楚，但与特定 DNA 序列的结合竞争以及通过 EVI-1 部分中的共抑制子 CtBP 招募组蛋白脱乙酰酶是显性负效应的可能潜在机制。其次，AML1/EVI-1 干扰 TGFbeta 信号传导并拮抗 TGFbeta 的生长抑制作用。 EVI-1 的第一个锌指结构域与 Smad3（一种 TGFb 信号转导器）相关联，并通过与 EVI-1 相互作用的 CtBP 募集组蛋白脱乙酰酶来抑制其转录活性。第三，AML1/EVI-1 阻断 JNK 活性并防止应激诱导的细胞凋亡。 AML1/EVI-1 通过 EVI-1 的第一个锌指结构域与 JNK 结合，并扰乱 JNK 与其底物之间的结合。最后，AML1/EVI-1通过激活依赖于EVI-1第二锌指结构域的c-Fos启动子来增强AP-1活性，并促进细胞增殖。所有这些功能共同促进AML1/EVI-1对造血干细胞的恶性转化。
The AML1/EVI-1 chimeric gene is generated by the t(3; 21)(q26; q22) translocation and plays a pivotal role in progression of hematopoietic stem cell malignancies such as chronic myelocytic leukemia and myelodysplastic syndrome. In AML1/EVI-1, an N-terminal half of AML1 including a runt homology domain is fused to the entire zinc-finger EVI-1 protein. AML1 is essential for hematopoietic cell development in fetal liver and its lineage-specific differentiation in adult. In contrast, EVI-1 is barely expressed in normal hematopoietic cells, but it is overexpressed in chronic myelocytic leukemia in blastic crisis and myelodysplastic syndrome-derived leukemia. There are at least four mechanisms identified in AML1/EVI-1 fusion protein that possibly lead into malignant transformation of hematopoietic stem cells. Firstly, AML1/EVI-1 exerts dominant-negative effects over AML1-induced transcriptional activation. Although target genes repressed by AML1/EVI-1 are still not known, binding competition to a specific DNA sequence and histone deacetylase recruitment through a co-repressor CtBP in EVI-1 part are conceivable underlying mechanisms for the dominant-negative effects. Secondly, AML1/EVI-1 interferes with TGFbeta signaling and antagonizes the growth-inhibitory effects of TGFbeta. The first zinc-finger domain of EVI-1 associates with Smad3, a TGFb signal transducer, and represses its transcriptional activity by recruiting histone deacetylase through CtBP that interacts with EVI-1. Thirdly, AML1/EVI-1 blocks JNK activity and prevents stress-induced apoptosis. AML1/EVI-1 associates with JNK through the first zinc-finger domain of EVI-1 and disturbs the association between JNK and its substrates. Lastly, AML1/EVI-1 enhances AP-1 activity by activating the c-Fos promoter depending on the second zinc-finger domain of EVI-1, and promotes cell proliferation. All these functions cooperatively contribute to the malignant transformation of the hematopoietic stem cells by AML1/EVI-1.