Molecular mechanisms of leukemic cell differentiation and apoptosis by retinoids.

视黄酸（RA）的生物学效应由两个不同的转录因子家族介导：视黄酸受体（RARs）和类维生素A X受体（RXRs）。以及来自异二聚体的RXR和RXR，并调节类视色素介导的基因表达。我们已经开发了几个系列的新型合成类视色素受体激动剂和拮抗剂，选择性地与RXR/RXR同源二聚体和RAR/RXR异源二聚体相互作用。使用这些化合物，我们证明RAR/RXR途径对白血病细胞的分化和增殖更重要。我们还发现RAR介导的信号通路在髓系白血病细胞的分化和凋亡中起重要作用。RXR的简单激活不足以诱导细胞凋亡。此外，转染bcl-2表达载体的HL-60细胞对类维生素A的分化反应与亲本HL-60细胞相同，尽管这些转染bcl-2的细胞中的凋亡被抑制，这表明在髓性白血病细胞中分化和凋亡是独立调节的。为了了解急性早幼粒细胞白血病（APL）中RA耐药的机制并寻找克服其耐药性的新方法，我们建立了第一个RA耐药的APL细胞系（UF-1）和人RA耐药的SCID小鼠模型。这些细胞系和动物模型可能是有用的研究在体外和体内的髓系白血病的生物学，以及评估新的治疗方法，包括RA耐药APL患者。

The biological effects of retinoic acid (RA) are mediated by two distinct families of transcription factors : retinoic acid receptors (RARs) and retinoid X receptors (RXRs). and RXRs and RXRs from heterodimers and regulate retinoid-mediated gene expression. We have developed several series of novel synthetic retinoid receptor agonists and antagonists that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. Using these compounds, we demonstrated that the RAR/RXR pathway is more important for differentiation and proliferation of leukemic cells. We also showed the RAR-mediated signaling pathway is important for differentiation and apoptosis of myeloid leukemic cells. Simple activation of RXRs is not sufficient to induce apoptosis of the cells. Furthermore, HL-60 cells transduced with bcl-2 expression vector showed the same differentiationresponse to retinoids as did parental HL-60 cells even though apoptosis was inhibited in these bcl-2 transduced cells, suggesting that differentiation and apoptosis are regulated independently in myeloid leukemic cells. To understand the mechanisms and identify novel approaches to overcome RA-resistance in acute promyelocytic leukemia (APL), we established the first RA-resistant APL cell line (UF-1) and human RA-resistant mouse model in SCID mice. These cell line and animal models may be useful for investigating the biology of myeloid leukemia in vitro and in vivo, as well as for evaluating novel therapeutoc approaches including patients with RA-resistant APL.