RETINOIC ACID RECEPTOR IN MYELOID LEUKEMIA

维甲酸（RA）诱导体外粒细胞分化 HL-60早幼粒细胞白血病细胞系是一个潜在的有吸引力的 用于治疗急性骨髓性白血病的替代治疗剂 白血病（AML），特别是早幼粒细胞（M3）型。 然而，RA的治疗功效受到以下因素的严重限制： 事实上，它不会诱导大多数其他类型的AML分化 细胞 利用逆转录病毒介导的基因转导，我们已经确定 视黄酸受体α（RAR-alpha）， 类固醇/甲状腺激素受体核转录超家族 因子，在介导RA诱导的 HL-60细胞粒系分化。 然而，不幸的是，大多数 骨髓性白血病细胞，包括那些明显对RA无反应的细胞， 也表达RA受体α mRNA。 我们希望确定一些AML 细胞对RA诱导的终末分化敏感， 有些则不然。 我们将确定RA耐药的髓系白血病 在RA受体本身中表现出结构和功能异常， 含有其他因素，如甲状腺激素受体或“显性” 负性”RA受体突变可能负性调节活性 正常RA受体，或表现出分子事件的差异 发生在RA受体激活的“下游”。 我们亦会评估 不同RA受体（RAR-α，β， γ和RXR-α）。 这些研究应该有助于 确定RA诱导分化和RA诱导分化的分子基础。 髓系白血病细胞的耐药性。 此外，关于甲状腺的研究 维生素A-视黄酸受体相互作用应提供相当大的 深入了解这些重要的转录因子在 造血细胞生长和分化。

Retinoic acid (RA) induces the in vitro granulocytic differentiation of the HL-60 promyelocytic leukemia cell line and is a potentially attractive alternative therapeutic agent for the treatment of acute myelogenous leukemia (AML) particularly of the promyelocytic (M3) variety. Nevertheless, the therapeutic efficacy of RA is severely limited by the fact that it does not induce differentiation of most other types of AML cells. Utilizing retroviral-mediated gene transduction we have determined that the retinoic acid receptor alpha (RAR-alpha), a member of the steroid/thyroid hormone receptor superfamily of nuclear transcription factors, plays a critical and central role in mediating RA-induced granulocytic differentiation of HL-60 cells. Paradoxically, however, most myeloid leukemia cells, including those that are clearly RA-unresponsive, also express RA receptor alpha mRNA. We wish to determine whey some AML cells are sensitive to RA-induced terminal differentiation while most others are not. We will determine whether RA-resistant myeloid leukemias exhibit structural and functional abnormalities in the RA receptor itself, harbor other factors such as thyroid hormone receptors or "dominant negative" RA receptor mutations which may negatively regulate the activity of normal RA receptors, or exhibit differences in molecular events occurring "downstream" of RA receptor activation. We will also assess the tissue specific activity of the different RA receptors (RAR- alpha, beta, gamma and RXR-alpha) in hematopoietic cells. These studies should help determine the molecular basis for both RA-induced differentiation and RA- resistance of myeloid leukemia cells. Moreover, the studies on thyroid hormone-retinoic acid receptor interaction should provide considerable insight into the role these important transcription factors play in hematopoietic cell growth and differentiation.