Guidez F, Ivins S, Zhu J, Söderström M, Waxman S, Zelent A
Leukaemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
Blood. 1998 Apr 15;91(8):2634-42.
Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARalpha fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARalpha fusion protein. Both PML- and PLZF-RARalpha possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARalpha protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARalpha, it had a very little effect on its association with the PLZF-RARalpha fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARalpha fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARalpha on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARalpha-associated leukemias to ATRA.
典型的急性早幼粒细胞白血病（APL）与PML-RARα融合蛋白的表达以及对全反式维甲酸（ATRA）治疗的反应性相关。已描述了一种罕见但复发性的APL，其对ATRA治疗无反应，并与一种变异的染色体易位以及PLZF-RARα融合蛋白的表达相关。PML-RARα和PLZF-RARα均具有相同的RAR序列，并抑制ATRA诱导的基因转录以及细胞分化。我们现在表明，上述致癌融合蛋白与核受体共抑制因子N-CoR相互作用，并且与野生型RARα蛋白相比，它们的相互作用对ATRA的敏感性降低。尽管药理学浓度的ATRA仍可诱导N-CoR从PML-RARα上解离，但对其与PLZF-RARα融合蛋白的结合影响甚微。N-CoR与PLZF-RARα之间这种对ATRA不敏感的相互作用是由嵌合体的N端PLZF部分介导的。似乎N-CoR/组蛋白去乙酰化酶共抑制因子复合物以对ATRA不敏感的方式直接与野生型PLZF蛋白的BTB/POZ结构域相互作用，并且至少部分是其作为转录抑制因子发挥功能所必需的。正如上述结果所预测的，组蛋白去乙酰化酶抑制剂可拮抗PML-RARα融合蛋白的致癌活性，并部分缓解PLZF的转录抑制作用以及PLZF-RARα对ATRA反应的抑制作用。综上所述，我们的结果证明核受体共抑制因子/组蛋白去乙酰化酶复合物参与了APL的分子发病机制，并为PML-RARα和PLZF-RARα相关白血病对ATRA的不同敏感性提供了解释。
