Molecular mechanisms of leukemic cell differentiation and apoptosis by retinoids.

维甲酸（retinoic acid， RA）的生物学效应是由两个不同的转录因子家族介导的：维甲酸受体（retinoic acid receptor, RARs）和维甲酸X受体（retinoid X receptor, RXRs）。RXRs和RXRs来自异源二聚体，并调节类视黄酮介导的基因表达。我们已经开发了一系列新的合成类视黄醇受体激动剂和拮抗剂，它们选择性地与RXR/RXR同型二聚体和RAR/RXR异源二聚体相互作用。使用这些化合物，我们证明了RAR/RXR通路对白血病细胞的分化和增殖更重要。我们还发现rar介导的信号通路对髓系白血病细胞的分化和凋亡很重要。单纯激活RXRs不足以诱导细胞凋亡。此外，用bcl-2表达载体转导的HL-60细胞对类维生素a表现出与亲本HL-60细胞相同的分化反应，尽管这些bcl-2转导的细胞的凋亡受到抑制，这表明髓系白血病细胞的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）抗ra的机制并找到克服ra耐药的新方法，我们在SCID小鼠中建立了首个ra耐药APL细胞系（UF-1）和人类ra耐药小鼠模型。这些细胞系和动物模型可能有助于体外和体内研究髓性白血病的生物学，以及评估包括ra耐药APL患者在内的新治疗方法。

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.