MECHANISMS OF TRANSFORMATION OF HEMOPOIETIC CELLS

癌症的特征是正常细胞的异常利用， 信号转导途径 造血细胞需要生长因子 for their其self-renewal自我renewal更新and differentiation分化. 白细胞介素-3（IL-3）是一种 由活化的T细胞分泌的细胞因子，其支持 造血前体细胞 使用非转化的IL 3依赖性鼠 细胞系，代表早期造血细胞，我们已经分离 致瘤的因子非依赖性转化体。 不像 亲本细胞，分泌IL-3的因子非依赖性细胞， 在IL-3位点重排，并过表达IL-3受体。 因此，我们认为它们是通过自分泌机制转化的。 本建议的目的是阐明这些机制， 而类似的造血细胞则变成恶性的。 为了实现这一 目标，提出了以下具体目标：目标1。以确定 IL-3表达激活的机制，目的2.以确定 IL-3基因重排是否足以将细胞转化为 因子独立性，目标3。为了确定是否增加了 IL-3受体与转化相关，目的4。到 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。 艾姆湖将考验 假设脑池内A型颗粒转座到 IL-3基因座的3'侧作为增强子或置换DNA 与mRNA稳定性有关的序列，从而延长IL-3 表情 目标2.将测试的假设，重新安排的 IL-3基因使因子依赖性细胞能够在缺乏IL-3的情况下生长。 外源性IL-3也导致恶性转化。 目标3。将 测试假设，与增加的表达一致， IL-3基因，同源受体的上调通常是必要的， 自分泌转化，目的4.将检验废除 因子依赖性的出现往往是由于插入 诱变 IL-3基因激活机制的研究进展 和重排，这发生在一些鼠因子依赖性细胞中， 人急性淋巴细胞白血病，可能有助于发病机制， 预防和治疗造血恶性肿瘤，并将提供 了解正常和异常的调节机制 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.