Repression of RUNX1 activity by EVI1: A new role of EVI1 in leukemogenesis
Repression of RUNX1 activity by EVI1: A new role of EVI1 in leukemogenesis
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DOI：
10.1158/0008-5472.can-06-3962
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Nucifora, Giuseppina
中科院分区：
文献类型：
--
作者：
Senyuk, Vitalyi;Sinha, Kislay K.;Nucifora, Giuseppina
在人类白血病中观察到的反复染色体易位通常会导致融合蛋白（DNA 结合转录因子）的表达。这些改变的蛋白质获得新的二聚化特性，导致不适当的多聚体转录复合物的组装，从而失调造血程序并诱导白血病发生。最近，我们报道了融合蛋白 AML1/MDS1/EVI1 (AME)，是与慢性粒细胞白血病和急性粒细胞白血病相关的 t(3;21)(q26;q22) 的产物，表现出复杂的自我相互作用模式。在这里，我们发现 MDS1/EVI1 的第 8 个锌指基序是一个寡聚结构域，不仅涉及 AME 与其自身的相互作用，而且还涉及与亲本蛋白 RUNX1 和 MDS1/EVI1 的相互作用，从中产生 AME。由于第 8 个锌指基序也存在于癌蛋白 EVI1 中，因此我们在体外和体内评估了 RUNX1 和 EVI1 之间相互作用的影响。我们发现，在体外，这种相互作用改变了RUNX1与DNA结合和调节报告基因的能力，而在体内，EVI1分离的第8个锌指基序的表达足以阻断粒细胞集落刺激因子诱导的32DcI3细胞分化，导致细胞死亡。由于在正常骨髓细胞中未检测到 EVI1，这些数据表明，其不适当表达可能部分通过涉及 EVI1 与关键造血调节因子关联的新机制促进造血转化，从而导致其功能受损。
Recurring chromosomal translocations observed in human leukemia often result in the expression of fusion proteins that are DNA-binding transcription factors. These altered proteins acquire new dimerization properties that result in the assembly of inappropriate multimeric transcription complexes that deregulate hematopoietic programs and induce leukemogenesis. Recently, we reported that the fusion protein AML1/MDS1/EVI1 (AME), a product of a t(3;21)(q26;q22) associated with chronic myelogenous leukemia and acute myelogenous leukemia, displays a complex pattern of self-interaction. Here, we show that the 8th zinc finger motif of MDS1/EVI1 is an oligomerization domain involved not only in interaction of AME with itself but also in interactions with the parental proteins, RUNX1 and MDS1/EVI1, from which AME is generated. Because the 8th zinc finger motif is also present in the oncoprotein EVI1, we have evaluated the effects of the interaction between RUNX1 and EVI1 in vitro and in vivo. We found that in vitro, this interaction alters the ability of RUNX1 to bind to DNA and to regulate a reporter gene, whereas in vivo, the expression of the isolated 8th zinc finger motif of EVI1 is sufficient to block the granulocyte colony-stimulating factor-induced differentiation of 32DcI3 cells, leading to cell death. As EVI1 is not detected in normal bone marrow cells, these data suggest that its inappropriate expression could contribute to hematopoietic transformation in part by a new mechanism that involves EVI1 association with key hematopoietic regulators, leading to their functional impairment.