Role of retinoic acid receptor in normal and leukemic bone marrow stromal cells

视黄酸受体在正常和白血病骨髓基质细胞中的作用

• 批准号: 05670929
• 负责人: KIZAKI Masahiro
• 金额: $ 1.34万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670929/
• 关键词: Retinoic acid; Retinoic acid receptor; Differentiation; Stromal cell; Acute promyelocytic leukemia

Retinoic acid (RA) exhibits effect on the proliferation and differentiation of many hematopoietic cells. Despite information on the effects of RA on hematopoietic cellslittle is known about how RA acts on the bone marrow stromal cells. All-trans RA and 9-cis RA,a stereoisomer of all-trans RA,treatment of humen bone marrow stromal cell line KM101, which produces M-CSF and GM-CSF constitutively, enhanced mRNA levels of both cytokines in a dose-dependent manner. Both RA also stimulated M-CSF production from primary human bone marrow stromal cells. All-trans RA did not affect the expression of RAR and RXR mRNA,whereas 9-cis RA increased RXR mRNA expression in a dose-dependent manner, suggesting RXR-dependentpathway through RAR/RXR or RXR/RXR must be critical in the cytokine production from bone marrow stromal cells. Next, we have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. RXR-slective analogs had little ability to inhibit clonal growth and induce differentiation of leukemic cells. Howver, retinoid which activate both RAR/RXR and RXR/RXR dimers could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients with acute promyelocytic leukemia (APL). Thus, we conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells.

维甲酸（RA）对多种造血细胞的增殖和分化有影响。尽管关于RA对造血细胞的影响的信息，但关于RA如何作用于骨髓基质细胞的信息知之甚少。全反式维甲酸和全反式维甲酸的立体异构体9-顺式维甲酸处理人骨髓基质细胞系KM 101（其组成性产生M-CSF和GM-CSF）后，以剂量依赖方式增强两种细胞因子的mRNA水平。这两种RA也刺激M-CSF的生产从原代人骨髓基质细胞。全反式RA不影响RAR和RXR mRNA的表达，而9-顺式RA以剂量依赖的方式增加RXR mRNA的表达，表明RAR/RXR或RXR/RXR的RXR依赖性途径在骨髓基质细胞产生细胞因子中起关键作用。接下来，我们开发了几个系列的新型合成类视色素，它们选择性地与RXR/RXR同源二聚体和RAR/RXR异源二聚体相互作用。RXR选择性类似物几乎没有抑制白血病细胞克隆生长和诱导分化的能力。同时激活RAR/RXR和RXR/RXR二聚体的维甲酸可抑制HL-60细胞的克隆生长并诱导其分化。因此，我们得出结论，RAR/RXR通路比RXR/RXR通路更重要的急性髓系白血病细胞的分化和增殖。

项目成果

Kizaki M,et al: "Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells." Blood. 83. 3289-3297 (1994)

Kizaki M 等人：“新型视黄酸，9-顺式视黄酸，与全反式视黄酸结合，是视黄酸抗性 HL-60 细胞分化的有效诱导剂。”

Nakajima H,et al: "All-trans and 9-cis retinoic acid enhance 1, 25-dihydroxyvitamin D3 induced monocytic differentiation of U937 cells." Leuk Res,. (in press).

Nakajima H 等人：“全反式和 9-顺式视黄酸增强 1, 25-二羟基维生素 D3 诱导的 U937 细胞的单核细胞分化。”

Kizaki,M.,et al: "Novel retinoic acid,9-cis retinoic acid,in combination with all-trans retinoic acid is effective inducer of differentiation of retinoic acid-resistant HL-60 cells" Blood. in press.

Kizaki,M.,等人：“新型视黄酸，9-顺式视黄酸，与全反式视黄酸组合是视黄酸抗性HL-60细胞分化的有效诱导剂”血液。

Kizaki M,et al: "Mechanisms of retinoid resistance : possible role of cytochrome P450 and P-glycoprotein." Blood. 87. 725-733 (1996)

Kizaki M 等人：“类视黄醇耐药机制：细胞色素 P450 和 P-糖蛋白的可能作用。”

Kizaki M, et al.: "Effects of novel retinoid X receptor (RXR) selective ligands on myeloid leukemic differentiation and proliferation in vitro" Blood. (in press).

Kizaki M 等人：“新型视黄醇 X 受体 (RXR) 选择性配体对体外骨髓白血病分化和增殖的影响”血液。