The equilibrium and control of cell proliferation, Survival and death in chronic hematological neoplasms

在慢性淋巴细胞白血病(CLL)和慢性成人T细胞白血病(ATL)等慢性血液肿瘤中，细胞的增殖、存活和死亡可能保持良好的平衡。本研究旨在分析慢性血液肿瘤细胞增殖与死亡，尤其是程序性细胞死亡(细胞凋亡)的关系，以期阐明慢性血液肿瘤的病理特点，寻找治疗的新途径。首先，我们建立了无血清培养体系，在该体系中我们可以检测与细胞凋亡相关的几个因素。在CLL和ATL中，我们发现糖皮质激素和蛋白激酶A激活剂增加了细胞的凋亡率，而白介素2则减少了细胞的凋亡率。在ATL中，我们检测了在G1检查点调节细胞周期和控制细胞凋亡的p53基因的突变和缺失。P53基因改变在急性型和危象型ATL中常见，而在慢性型中不常见，提示P53基因改变与疾病的进展有关。此外，我们还发现34例T细胞淋巴瘤和白血病患者中有4例EBV基因组呈单一的异构体形式，提示EBV的潜伏基因产物或细胞癌基因参与了EBV感染后日本T细胞肿瘤的发生发展。这些观察表明，在慢性血液肿瘤中，几种内部和外部因素调节着细胞的增殖和死亡。

In chronic hematological neoplasmas such as chronic lymphocytic leukemia (CLL) and chronic type of adult T-cell leukemia (ATL) , it is likely that cell proliferation, survival and death keep good equilibrium in each. The aim of this study is analysis of the relationship between cell prolifeartion and death, particulaly programd cell death(apoptosis), in order to clarify the pathological features and to find new approach to therapy in chronic hematological neoplasms. Firstly, we established the serum free culture system in which we can examine several factors assoiated with the apoptosis. In CLL and ATL, we found that apoptosis is increased by corticosteroid and protein kinase A activator and decreased by interleukin 2. In ATL, we detected the mutation and deletion of the p53 gene, which regulate cell cycle at the Gl check point and control apoptosis. The alteration of p53 gene is frequently observed in acute and crisis type of ATL but not in chronic type, suggesting that the p53 gene alteration is assosiated with disease progression.In addition, we found EBV genome as a single episomal form is 4 out of 34 patients with T-cell lymphoma and leukemia, indicating that latent gene products of EBV or celluler oncogenes are involved in the development of Japanese T-cell neoplasm following EBV infection. These observations indicate that the several inner and outer factors regulate cell proliferation and death in chronic hematological neoplasms.