MECHANISMS OF TRANSFORMATION OF HEMOPOIETIC CELLS

癌症的特征是正常细胞的异常利用。 信号转导通路。造血细胞需要生长因子 为他们的自我更新和差异化。白介素3(IL3)是一种 活化的T细胞分泌的细胞因子，支持肿瘤的生长 造血祖细胞。使用未转化的白介素3依赖小鼠 代表早期造血细胞的细胞系，我们已经分离 具有致癌作用的非因子转化子。不像 亲代细胞是分泌IL-3的非因子细胞， IL-3基因重排，并过度表达IL-3受体。 因此，我们提出它们是通过自分泌机制转化的。 这项提案的目标是勾勒出以下机制 类似的造血细胞也会变得恶性。要做到这一点 目标，提出以下具体目标：目标1.确定 激活IL-3表达的机制，目的2.确定 IL-3基因重排是否足以将细胞转化为 因子独立性，目标3。确定增加的表达是否 IL-3受体与转化有关，目的4。 确定自发的、化学的和慢性的 逆转录病毒感染可激活IL-3基因表达。Aim L.将测试 假设脑池内A型粒子移位到 IL-3基因的3‘端既可以作为增强子，也可以取代DNA 与mRNA稳定性有关的序列，从而延长IL-3 表情。目标2.将检验这样一个假设，即 IL-3基因使依赖因子的细胞在缺乏 外源性IL-3也会导致恶性转化。目标3.意志 测试假设，与增加的表达相一致的 IL-3基因，同源受体的上调通常是必要的 自分泌转化，目标4.将检验废除的假设 因子依赖的结果通常是插入 诱变。对IL-3基因激活机制的认识 和重排，这发生在一些小鼠因子依赖的细胞和 人类急性淋巴细胞白血病，可能有助于发病， 预防和治疗血液系统恶性肿瘤，并将提供 对正常与异常调节机制的洞察 细胞生长。

Cancer is characterized by the aberrant utilization of normal cellular signal transduction pathways. Hemopoietic cells require growth factors for their self-renewal and differentiation. Interleukin-3 (IL-3) is a cytokine secreted by activated T cells which supports the growth of hemopoietic precursor cells. Using non-transformed IL3-dependent murine cell lines, which represent early hemopoietic cells, we have isolated factor-independent transformants which are tumorigenic. Unlike the parental cells, the factor-independent cells secreted IL-3, were rearranged at the IL-3 locus, and overexpressed the IL-3 receptor. Therefore, we proposed they were transformed by an autocrine mechanism. The goal of this proposal is to delineate the mechanisms by which these and similar hemopoietic cells are rendered malignant. To accomplish this objective, the following specific aims are proposed: Aim 1. To determine the mechanism of activation of IL-3 expression, Aim 2. To determine whether IL-3 gene rearrangement is sufficient to transform cells to factor-independence, Aim 3. To determine whether increased expression of the IL-3 receptor is associated with transformation, and Aim 4. To determine the mechanisms by which spontaneous, chemical and chronic retroviral infection can activate IL-3 gene expression. Aim l. will test the hypothesis that transposition of an intracisternal type A particle to the 3' side of the IL-3 locus acts either as an enhancer or displaces DNA sequences implicated in mRNA stability, thereby prolonging IL-3 expression. Aim 2. will test the hypothesis that rearrangement of the IL-3 gene enables factor-dependent cells to grow in the absence of exogenous IL-3 and also results in malignant transformation. Aim 3. will test the hypothesis, that in concert with the increased expression of the IL-3 gene, upregulation of the cognate receptor is often necessary for autocrine transformation, Aim 4. will test the hypothesis that abrogation of factor-dependency often occurs as the result of insertional mutagenesis. An understanding of the mechanisms of IL-3 gene activation and rearrangement, which occurs in some murine factor-dependent cells and human acute lymphocytic leukemias, may aid in the pathogenesis, prevention and treatment of hemopoietic malignancies and will provide insights into the mechanisms of regulation of normal and abnormal cellular growth.