AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein.
AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein.
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DOI：
10.1182/blood.v96.12.3939.h8003939_3939_3947
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发表时间：
2000-12
期刊：
影响因子：
20.3
通讯作者：
A. Melnick;A. Melnick;G. Carlile;G. Carlile;M. McConnell;M. McConnell;Adam Polinger;Adam Polinger;S. Hiebert;S. Hiebert;J. Licht;J. Licht
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文献类型：
--
作者：
A. Melnick;A. Melnick;G. Carlile;G. Carlile;M. McConnell;M. McConnell;Adam Polinger;Adam Polinger;S. Hiebert;S. Hiebert;J. Licht;J. Licht
AML-1/ETO融合蛋白是由M2型急性髓细胞性白血病（AML）中的（8;21）易位产生的，是AML-1的主要抑制形式。这种效应是由于蛋白质的ETO部分能够将共阻遏物募集到AML-1靶基因的启动子。t（11; 17）（q21; q23）相关的急性早幼粒细胞白血病产生早幼粒细胞白血病锌指PLZFt/RAR α融合蛋白，并以类似的方式抑制RAR α靶基因表达和骨髓分化。PLZF在造血祖细胞中表达，并通过抑制细胞周期蛋白A2和其他靶点作为生长抑制剂发挥作用。ETO是PLZF的辅阻遏物，并通过将PLZF连接到含组蛋白脱乙酰酶的复合物来增强转录抑制。在瞬时转染细胞和来自t（8;21）白血病患者的细胞系中，PLZF和AML-1/ETO形成紧密复合物。在瞬时测定中，AML-1/ETO阻断PLZF的转录抑制，即使是在相对于PLZF的亚化学计量水平。这种效应依赖于ETO锌指结构域的存在，其招募辅阻遏物，并且不能通过通常增强PLZF阻遏的辅阻遏物的过表达来拯救。AML-1/ETO还将PLZF从核基质中排除，并降低其与同源DNA结合位点结合的能力。最后，ETO与PLZF/RAR α相互作用，并通过RARE增强其抑制能力。这些数据显示了M2和M3白血病的转录途径中的联系。（血。2000;96：3939-3947）
The AML-1/ETO fusion protein, created by the (8;21) translocation in M2-type acute myelogenous leukemia (AML), is a dominant repressive form of AML-1. This effect is due to the ability of the ETO portion of the protein to recruit co-repressors to promoters of AML-1 target genes. The t(11;17)(q21;q23)-associated acute promyelocytic leukemia creates the promyelocytic leukemia zinc finger PLZFt/RAR alpha fusion protein and, in a similar manner, inhibits RAR alpha target gene expression and myeloid differentiation. PLZF is expressed in hematopoietic progenitors and functions as a growth suppressor by repressing cyclin A2 and other targets. ETO is a corepressor for PLZF and potentiates transcriptional repression by linking PLZF to a histone deacetylase-containing complex. In transiently transfected cells and in a cell line derived from a patient with t(8;21) leukemia, PLZF and AML-1/ETO formed a tight complex. In transient assays, AML-1/ETO blocked transcriptional repression by PLZF, even at substoichiometric levels relative to PLZF. This effect was dependent on the presence of the ETO zinc finger domain, which recruits corepressors, and could not be rescued by overexpression of co-repressors that normally enhance PLZF repression. AML-1/ETO also excluded PLZF from the nuclear matrix and reduced its ability to bind to its cognate DNA-binding site. Finally, ETO interacted with PLZF/RAR alpha and enhanced its ability to repress through the RARE. These data show a link in the transcriptional pathways of M2 and M3 leukemia. (Blood. 2000;96:3939-3947)