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Molecular mechanisms of leukemic cell differentiation and apoptosis by retinoids.

类视黄醇白血病细胞分化和凋亡的分子机制。

基本信息

批准号：
08671257
负责人：
KIZAKI Masahiro
金额：
$ 1.6万
依托单位：
Department of Internal Medicine, Keio University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

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.

视黄酸 (RA) 的生物效应由两个不同的转录因子家族介导：视黄酸受体 (RAR) 和类视黄酸 X 受体 (RXR)。 RXR 和来自异二聚体的 RXR 并调节类维生素A介导的基因表达。我们开发了多个系列的新型合成类视黄醇受体激动剂和拮抗剂，它们选择性地与 RXR/RXR 同二聚体和 RAR/RXR 异二聚体相互作用。使用这些化合物，我们证明 RAR/RXR 途径对于白血病细胞的分化和增殖更为重要。我们还表明 RAR 介导的信号通路对于骨髓白血病细胞的分化和凋亡很重要。 RXR 的简单激活不足以诱导细胞凋亡。此外，用bcl-2表达载体转导的HL-60细胞显示出与亲本HL-60细胞相同的对类维生素A的分化反应，尽管这些bcl-2转导的细胞中的细胞凋亡受到抑制，这表明骨髓白血病细胞中的分化和细胞凋亡是独立调节的。为了了解急性早幼粒细胞白血病 (APL) 的机制并确定克服 RA 耐药性的新方法，我们在 SCID 小鼠中建立了第一个 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研究骨髓性白血病的体外和体内生物学，以及评估新的治疗方法，包括 RA 耐药 APL 患者。