Role of the histone deacetylase complex in acute promyelocytic leukaemia
Role of the histone deacetylase complex in acute promyelocytic leukaemia
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DOI：
10.1038/35895
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发表时间：
1998-02-19
期刊：
影响因子：
64.8
通讯作者：
Evans, RM
中科院分区：
文献类型：
--
作者：
Lin, RJ;Nagy, L;Evans, RM
非配体维甲酸受体（RARs）通过一类被称为SMRT或N-CoR4的沉默介质募集组蛋白去乙酰化酶复合体（1-3）来抑制靶基因的转录。RAR α的突变形式，由染色体易位与PML（早幼粒细胞白血病）（6-8）或PLZF（早幼粒细胞白血病锌指）（9,10）位点的易位产生，是致癌的，并导致人类急性早幼粒细胞白血病（APL）。PML-RAR α APL患者在使用药理学剂量的视黄酸（RA）治疗后实现完全缓解；相比之下，PLZF-RAR α患者反应非常差，如果有的话（11）。在这里，我们报道这两种嵌合受体与组蛋白去乙酰化酶（HDAC）复合物的关联有助于确定APL的发展和患者对类维生素a的反应能力。与这些观察结果一致，组蛋白去乙酰化酶抑制剂显著增强了类维甲酸诱导的ra敏感的分化，并恢复了ra耐药的APL细胞系的类维甲酸反应。我们的研究结果表明，致癌RARs通过异常的染色质乙酰化介导白血病的发生，并且核受体辅助因子的药理学操作可能是治疗人类疾病的有用方法。
Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex(1-3) through a class of silencing mediators termed SMRT or N-CoR4,5. Mutant forms of RAR alpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia)(6-8) or the PLZF (for promyelocytic leukaemia zinc finger)(9,10) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RAR alpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RAR alpha patients respond very poorly, if at all(11). Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation, of nuclear receptor co-factors may be a useful approach in the treatment of human disease.