Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO
Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO
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DOI：
10.1128/mcb.18.12.7185
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发表时间：
1998-12-01
影响因子：
5.3
通讯作者：
Lazar, MA
中科院分区：
文献类型：
--
作者：
Gelmetti, V;Zhang, JS;Lazar, MA
急性早幼粒细胞白血病视黄酸受体融合蛋白的生物学活性离不开核受体辅阻遏物（CoR）-组蛋白去乙酰化酶（HDAC）复合物的募集。我们在这里报告ETO（8 - 21或MTG 8），这是融合到急性髓细胞性白血病1（AML 1）转录因子在t（8;21）AML，通过其锌指区与辅阻遏物N-CoR和SMRT的保守结构域相互作用，并在体内招募HDAC。融合蛋白AML 1-ETO保留了ETO与N-CoR/SMRT和HDAC形成稳定复合物的能力。ETO C末端的缺失消除了CoR结合和HDAC募集，并严重损害了AML 1-ETO抑制造血前体分化的能力。这些数据表明，与CoR-HDAC形成稳定的复合物对ETO激活AML 1的致白血病潜力至关重要，并表明辅阻遏物复合物的异常募集是白血病发生的一般机制。
Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the retinoic acid receptor fusion proteins of acute promyelocytic leukemias. We report here that ETO (eight-twenty-one or MTG8), which is fused to the acute myelogenous leukemia 1 (AML1) transcription factor in t(8;21) AML, interacts via its zinc finger region with a conserved domain of the corepressors N-CoR and SMRT and recruits HDAC in vivo. The fusion protein AML1-ETO retains the ability of ETO to form stable complexes with N-CoR/SMRT and HDAC. Deletion of the ETO C terminus abolishes CoR binding and HDAC recruitment and severely impairs the ability of AML1-ETO to inhibit differentiation of hematopoietic precursors. These data indicate that formation of a stable complex with CoR-HDAC is crucial to the activation of the leukemogenic potential of AML1 by ETO and suggest that aberrant recruitment of corepressor complexes is a general mechanism of leukemogenesis.