MECHANISMS UNDERLYING TUMOR DORMANCY

BCL1白血病是第一个在患有BCL1白血病的小鼠身上描述的B细胞白血病 在一只老年BALB/c小鼠中自发出现。一个单元格被转移到 同基因受者导致进行性白血病，总是可以检测到的 12周后出现进展性肿瘤生长和死亡。老鼠 致死X射线照射后呈现的H-2基因的嵌合体 注射T细胞耗尽的同种异体骨髓允许进行性 随后注射的BCL1细胞的生长。然而，6周后， 肿瘤消退，根据独特型分析判断，小鼠似乎没有肿瘤 血细胞、白血球计数和脾大小。疾病不会发生 只要对小鼠进行了跟踪(8个月)。尽管如此，细胞 转移研究表明，脾中的肿瘤负荷相对较大(10-6 -10-7个细胞)。我们将研究肿瘤休眠的生物学，试图 回答以下问题：1)患者的细胞周期状态如何 休眠细胞？2)它们是否与初始种群不同 根据免疫表型、对淋巴因子的反应和核型判断？3)什么 诱导休眠所需的寄主防御机制是什么？ 休眠的自然历史是什么，例如，休眠的BCL1细胞 最终死亡，还是当免疫应答开始增长时 随年龄增长而减少？5)什么干扰会引发肿瘤生长？ 针对bcl1的免疫毒素能在体内消除这种休眠群体吗？ 关于肿瘤休眠的同源模型，对bcl1的免疫 在之前免疫的两只BALB/c小鼠中都产生了肿瘤 纯化的bcl1-IgMlambda和未免疫的同源小鼠(B.A.20) 在IGH轨迹上有所不同。我们将进一步开发这两个模型系统，以 研究肿瘤休眠。

BCL1 leukemia is the first B cell leukemia to be described in mice having arisen spontaneously in an elderly BALB/c mouse. One cell transferred to a syngeneic recipient causes progressive leukemia that is always detectable by 12 weeks and is followed by progressive tumor growth and death. Mice rendered chimeric at the H-2 locus by lethal X-irradiation followed by injection of T cell depleted allogeneic bone marrow allow progressive growth of subsequently injected BCL1 cells. However, after 6 weeks, the tumor recedes and the mice appear tumor-free as judged by idiotype analysis of blood cells, white blood count, and spleen size. Disease does not occur for as long as the mice have been followed (8 months). Nevertheless, cell transfer studies indicate a relatively large tumor load in the spleen (10-6 - 10-7 cells). We will study the biology of tumor dormancy in attempts to answer the following questions: 1) What is the cell cycle status of the dormant cells? 2) Are they different from the starting population as judged by immunophenotype, response to lymphokines and karyotype? 3) What are the host defense mechanisms that are required to induce dormancy? 4) What is the natural history of dormancy, e.g. do dormant BCL1 cells eventually die or do they begin to grow when immune responsiveness decreases with age? 5) What perturbations can initiate tumor growth? 6) Can immunotoxins specific to BCL1 eliminate this dormant population in vivo? With regard to a syngeneic model of tumor dormancy, immunity to the BCL1 tumor has been generated in both BALB/c mice previously immunized with purified BCL1-IgMlambda and in non-immunized congenic mice (B.A. 20) that differ at the IgH locus. We will further develop these 2 model systems to study tumor dormancy.