Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci P G, Lazar M A
Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
Mol Cell Biol. 1998 Dec;18(12):7185-91. doi: 10.1128/MCB.18.12.7185.
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.
核受体共抑制因子（CoR）-组蛋白去乙酰化酶（HDAC）复合物的募集对于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不可或缺。我们在此报告，在t(8;21)急性髓系白血病中与急性髓系白血病1（AML1）转录因子融合的ETO（八二十一或MTG8），通过其锌指区域与共抑制因子N-CoR和SMRT的保守结构域相互作用，并在体内募集HDAC。融合蛋白AML1-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AML1-ETO抑制造血前体细胞分化的能力。这些数据表明，与CoR-HDAC形成稳定复合物对于ETO激活AML1的白血病发生潜能至关重要，并提示共抑制因子复合物的异常募集是白血病发生的普遍机制。
