The Role of Cyclin A1 in Acute Myeloid Leukemia

描述（由申请人提供）：我们已经确定了一种新的哺乳动物a型细胞周期蛋白，细胞周期蛋白AI，我们在小鼠中的靶向突变显示，它对于雄性生殖细胞进入减数分裂的进程至关重要。人类细胞周期蛋白AI也在髓性白血病细胞系和急性髓性白血病患者的白血病细胞中高度表达，特别是早幼粒细胞形式（APL）。我们已经验证了一个假设，即异常高水平的细胞周期蛋白AI是导致白血病表型的原因，即作为致癌基因。在人组织蛋白酶G启动子的控制下，在骨髓前体细胞中产生了cyclin AI表达的转基因小鼠。他们表现出异常的骨髓生成，并发展为低外显率和长潜伏期的急性髓性白血病。有趣的是，在转基因小鼠模型和人NB4细胞中，细胞周期蛋白A1的定位主要是细胞质，而不是生殖细胞中的核定位。我们希望了解骨髓形成的细胞机制，在细胞周期蛋白A1水平升高的情况下发生改变，现在主要是细胞质。我们将研究细胞周期蛋白A1的独特细胞质定位，以验证这一特性有助于肿瘤发生的假设。我们还将通过研究细胞周期蛋白A1基因缺失小鼠的造血参数来解决细胞周期蛋白A1在正常造血过程中的作用。细胞周期蛋白A1在正常细胞和白血病细胞中具有不同的Cdk伴侣、其他相互作用伴侣和底物的假设将使用免疫沉淀和酵母2杂交筛选进行测试。由于高水平的细胞周期蛋白A1已被证明是APL的特征，我们将询问操纵细胞周期蛋白A1的表达是否会影响白血病的发展。我们将通过进行遗传学研究来测试这一想法，我们将在融合癌基因x - rar α转基因APL动物模型中操纵细胞周期蛋白A1的表达。问题是，在缺乏细胞周期蛋白AI的情况下，这些小鼠是否会更能抵抗白血病的发展。这些研究将为髓性白血病的病因学、细胞周期控制在癌变过程中的作用以及开发新的、潜在的高度组织特异性靶标分子提供重要的见解。

DESCRIPTION (provided by applicant): We have identified a novel mammalian A-type cyclin, cyclin AI, that our targeted mutagenesis in mice revealed to be essential for the progression of male germ cells into meiosis. Human cyclin AI is also highly expressed in myeloid leukemia cell lines and in leukemic cells from patients with acute myeloid leukemias, in the promyelocytic form (APL) in particular. We have tested the hypothesis that the aberrant high levels of cyclin AI were causal in the leukemic phenotype, i.e., acting as an oncogene. Transgenic mice in which cyclin AI was expressed under the control of the human cathepsin G promoter in myeloid precursor cells were generated. They exhibited abnormal myelopoiesis and developed acute myeloid leukemia with low penetrance and long latency. Interestingly, in the transgenic mouse model and in human NB4 cells, the localization of cyclin A1 is predominantly cytoplasmic, distinct from its nuclear localization in germ cells. We wish to understand the cellular mechanisms in myelopoiesis that are altered in the presence of elevated levels of cyclin A1 that is now mostly cytoplasmic. The distinct cytoplasmic localization of cyclin A1 will be studied, testing the hypothesis that this property contributes to the tumorigenesis. We will also address the role of cyclin A1 during normal hematopoiesis by studying hematopoietic parameters in mice that are null for the cyclin A1 gene. The hypothesis that cyclin A1 will have distinct Cdk partners, other interacting partners, and substrates in normal versus leukemic cells will be tested using immunoprecipitation and a yeast 2-hybrid screen. As high levels of cyclin A1 protein have been shown to be characteristic of APL, we will ask whether manipulating the expression of cyclin A1 will affect the development of the leukemia. We will test this idea by performing genetic studies in which we will manipulate the expression of cyclin A1 in the fusion oncogene X-RARalpha transgenic animal models of APL. The question is whether these mice will be more resistant to the development of leukemia in the absence of cyclin AI. These studies will provide important insight into the etiology of myeloid leukemia, the role of cell cycle control in the oncogenic process, and the development of new and potentially highly tissue-specific target molecules for pharmacologic intervention.