MULTISTEP LYMPHOMAGENESIS

淋巴细胞发生是一个复杂的多步骤过程，其中淋巴细胞信号通路、转录调控和凋亡机制的失调导致转化。在这项资助的最初阶段，我们建立在对自然发生的牛伪白血病综合征的观察和对人类肿瘤标本的研究的基础上，开发了一个模型系统来研究人类肿瘤标本的调节丝氨酸研究的作用，开发了一个模型系统来研究调节丝氨酸-苏氨酸激酶CK2（以前称为酪蛋白激酶II）在淋巴瘤形成中的作用。这些实验表明，CK2alpha表达失调实际上确实易患淋巴瘤，并且CK2alpha过表达与肿瘤抑制基因p53缺乏协同作用，加速淋巴瘤的发生。进一步的实验表明，ck2 α淋巴瘤组成性上调一系列淋巴细胞转录因子家族，包括AP-1、NFkappaB、CREB、NFAT和TCF/LEF。正常情况下，这些因素似乎参与淋巴细胞的生理激活反应，而不是恶性生长控制。在本实验中，CK2alpha在体外和体内直接或间接调节这些转录因子对淋巴细胞转化的作用。为了用遗传方法回答CK2alpha对正常淋巴细胞生长有多重要的问题，我们将开发一个CDK2alpha“敲除”小鼠模型。我们还将在转基因和基因敲除实验的结合中评估其他CK2亚基，CK2alpha'和CK2beta对淋巴细胞生长和发育的影响。这些研究将充分阐明CK2亚基在淋巴细胞发育和转化中的作用，并将为本构表达的转录激活因子可能对淋巴瘤发生的致病作用提供重要的新见解。除了扩大我们对淋巴细胞生长控制途径的理解外，希望这些研究将有助于未来开发新的抗肿瘤疗法，针对已证实的激酶CDK2本身或协同致癌转录因子。

Lymphogenesis is a complex multi-step process in which dysregulation of lymphocyte signaling pathways, transcriptional regulation, and apoptosis machinery leads to transformation. In the initial period of this grant, we built upon observations from a naturally-occurring bovine pseudo- leukemia syndrome and from studies of human tumor specimens to develop a model system to investigate the role of the regulatory serine studies of human tumor specimens to develop a model system to investigate the role of the regulatory serine-threonine kinase CK2 (formerly termed casein kinase II) in lymphomagenesis. These experiments have shown that dysregulated expression of CK2alpha does in fact predispose to lymphoma, and that CK2alpha over-expression synergizes with deficiency of the tumor suppressor gene p53 to accelerate lymphomagenesis. Further experiments have demonstrated that CK2alpha lymphomas constitutively up-regulate a panel of lymphocyte transcription factor families including AP-1, NFkappaB, CREB, NFAT, and TCF/LEF. Normally, these factors appear to be involved in physiological activation responses of lymphocytes rather than in malignant growth control. In the proposed experiments, the role of CK2alpha in the direct or indirect regulation of these transcriptional factors to lymphocyte transformation in vitro and in vivo. To answer the question of how essential CK2alpha is to normal lymphocyte growth using a genetic approach, we will develop a CDK2alpha "knockout" mouse model. We will also assess the impact of the other CK2 subunits, CK2alpha' and CK2beta, upon lymphocyte growth and development in a combination of transgenic and knockout experiments. These studies will fully elucidate the role of the CK2 subunits in lymphocyte development and transformation, and will also provide important new insights into the pathogenic contribution that constitutively expressed transcriptional activators may make to lymphomagenesis. In addition to expanding our understanding of growth control pathways in lymphocytes, it is hoped that these studies will contribute to the development of new anti-tumor therapies in the future, directed against proven kinase CDK2 itself or collaborating oncogenic transcription factors.