MATURATION OF HUMAN MYELOID LEUKEMIA

我们正在继续研究磷脂的作用， CA2个以上- 依赖性蛋白激酶（蛋白激酶C）在成熟 白血病细胞转化为巨噬细胞 过去一年在许多国家产生的数据 实验室，包括我们自己的实验室，证实了我们的假设。 原用途：蛋白激酶C是佛波醇二酯受体。 我们已经合成了化学定义的二酰基甘油，并证明它们是 “内源性磷酸酶”，如通过它们的以下能力所证明的：（1）激活 蛋白激酶C;（2）竞争性抑制放射性标记的佛波醇二酯 与可溶性或细胞佛波醇二酯受体结合;（3）诱导 白血病细胞分化为巨噬细胞;（4）模拟佛波醇 二酯诱导的磷蛋白变化发生在巨噬细胞 分化 生物活性佛波醇二酯和细胞渗透性 二酰基甘油诱导Mr = 21，52，65， 和80千道尔顿 32P负载的HL-60细胞。 今年，重点将 用于从HL-60细胞和抗体中纯化蛋白激酶C 生产 主要的磷蛋白将被纯化， 32对氨基 确定了酸和肽图谱。 该项目的长期目标是开始了解骨髓 在生化水平上成熟。 主要科学学科 涉及血液学、肿瘤学和细胞生物学。 体外成熟 早幼粒细胞白血病细胞作为骨髓模型 分化 像这样的研究可以定义分子缺陷 这导致骨髓成熟的停止并因此导致白血病。 的 调查是与健康有关的，因为它探索了一个分子途径， 在白血病中被阻断的分化。 作为以下物质诱导剂的活性剂 细胞成熟将很快在实验中找到临床应用， 治疗白血病和其他恶性肿瘤。 （B）

We are continuing to investigate the role of phospholipid and Ca2+-dependent protein kinase (protein kinase C) in the maturation of leukemia cells into macrophages. Data generated over the past year in many laboratories, including our own, confirm the hypothesis put forth in our original application: protein kinase C is the phorbol diester receptor. We have synthesized chemically defined diacylglycerols and shown them to be the "endogenous phorbols" as evidenced by their ability to: (1)\activate protein kinase C; (2)\competitively inhibit radiolabeled phorbol diester binding to the soluble or cellular phorbol diester receptor; (3)\induce leukemic cells to differentiate into macrophages; and (4)\mimic phorbol diester-induced phosphoprotein changes that occur during macrophage differentiation. Biologically active phorbol diesters and cell-permeable diacylglycerols induce phosphorylation of proteins with Mr = 21, 52, 65, and 80 kilodaltons in 32P-loaded HL-60 cells. This year, emphasis will be placed on purification of protein kinase C from HL-60 cells and antibody production. The major phosphoproteins will be purified and 32P amino acids and peptide maps determined. The long-term objective of this project is to begin to understand myeloid maturation at a biochemical level. The major scientific disciplines involved are hematology, oncology, and cell biology. In vitro maturation of promyelocytic leukemia cells serves as a model for bone marrow differentiation. Studies such as these may define the molecular defect which leads to cessation of myeloid maturation and hence, leukemia. The investigation is health-related because it explores a molecular pathway of differentiation which is blocked in leukemia. Agents active as inducers of cell maturation will soon find clinical application in the experimental treatment of leukemia and other malignancies. (B)