Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara F F, Zamir I, Seiser C, Grignani F, Lazar M A, Minucci S, Pelicci P G
Istituto di Medicina Interna e Scienze Oncologiche, Perugia University, Italy.
Nature. 1998 Feb 19;391(6669):815-8. doi: 10.1038/35901.
The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RARalpha). These proteins retain the RARalpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARalpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RARalpha APLs, whereas PLZF-RARa APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here we show that both PML-RARalpha and PLZF-RARalpha fusion proteins recruit the nuclear co-repressor (N-CoR)-histone deacetylase complex through the RARalpha CoR box. PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RARalpha, but not from PLZF-RARalpha. Mutation of the N-CoR binding site abolishes the ability of PML-RARalpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RARalpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RARalpha and PLZF-RARalpha co-repressor complexes determines the differential response of APLs to RA.
急性早幼粒细胞白血病（APL）的转化蛋白是早幼粒细胞白血病（PML）和早幼粒细胞白血病锌指（PLZF）蛋白与维甲酸受体α（RARα）的融合蛋白。这些蛋白保留了RARα的DNA结合域和维甲酸（RA）结合域，并且它们阻断造血分化的能力取决于RARα的DNA结合域。因此，RA靶基因是下游效应器。然而，用RA治疗可诱导PML-RARα APLs中的白血病原始细胞分化并使疾病缓解，而PLZF-RARα APLs对RA耐药。RARs的转录调控涉及组蛋白去乙酰化酶对染色质的修饰，这些酶由核共抑制因子募集到RA靶基因。我们在此表明，PML-RARα和PLZF-RARα融合蛋白均通过RARα共抑制因子框募集核共抑制因子（N-CoR）-组蛋白去乙酰化酶复合物。PLZF-RARα在PLZF氨基末端区域含有第二个RA抗性结合位点。高剂量的RA可从PML-RARα释放组蛋白去乙酰化酶活性，但不能从PLZF-RARα释放。N-CoR结合位点的突变消除了PML-RARα阻断分化的能力，而组蛋白去乙酰化酶活性的抑制将PLZF-RARα的转录和生物学效应从RA信号通路的抑制剂转变为激活剂。因此，组蛋白去乙酰化酶的募集对于APL融合蛋白的转化潜能至关重要，并且RA对PML-RARα和PLZF-RARα共抑制复合物稳定性的不同影响决定了APLs对RA的不同反应。
