DORMANT LYMPHOMA CELLS (DLC) FROM MICE

BCL1是一种高度恶性的可移植的小鼠B细胞淋巴瘤 通常在6-8周内对小鼠致命。我们已经开发了两种型号的 BCL1小鼠肿瘤休眠：预先免疫BALB/c小鼠 Bcl1-免疫球蛋白或被动注射小鼠多克隆抗体 SCID小鼠的独特型。在这两种模型中，大多数小鼠都有1-3个 X 106个BCL1细胞在其脾中休眠数月。有一个 在一年半内逐渐但缓慢地解除休眠 观察。利用高分辨率多参数流式细胞术 在细胞分析和分选方面，我们成功地分离和 分析休眠淋巴瘤细胞的数量。初步研究 使用DNA染料(Hoechst)和给药BrdU表明 很高比例的休眠细胞是非周期细胞。在建议的 研究，我们将确定休眠淋巴瘤细胞之间的差异， 在非免疫小鼠中生长的淋巴瘤细胞和在非免疫小鼠中生长的淋巴瘤细胞 以前处于休眠状态的小鼠，以努力阐明 休眠。因此，我们将把我们对细胞周期分析的研究扩展到 从它们的诱导开始确定休眠细胞的历史 从生长bcl1到它们在晚年失去休眠。我们会 确定上述三个群体是否存在差异 关于免疫表型，包括细胞因子受体，模式 细胞因子的产生和信使RNA的表达水平 似乎在B细胞生长中起作用的候选癌基因，例如， MYC、Bcl2、Rb、P53。我们将测定其在体内的分布 休眠细胞与器官部位和组织分布的关系 在脾内。我们将确定是否重新增长的人口 IS ID+不再易受抗-1的休眠诱导作用 身份证。根据我们的初步结果，我们的工作假设是： 大部分但不是全部BCL1细胞的细胞周期停滞导致休眠 由于ID免疫反应；这导致生长下调- 促进癌基因和抑制基因的上调；逃避 休眠的部分原因是休眠的bcl1的子集发生突变 还在骑车。将要进行的研究将检验这些假设 应该会产生新的关于肿瘤潜在机制的研究 休眠。

BCL1 is a high grade transplantable murine B cell lymphoma that is normally lethal for mice in 6-8 weeks. We have developed two models of tumor dormancy in BCL1 mice: prior immunization of BALB/c mice with BCL1-immunoglobulin or passive administration of murine polyclonal anti- idiotype in SCID mice. In both models, the majority of mice harbor 1-3 x 106 dormant BCL1 cells in their spleens for many months. There is a progressive but slow loss of dormancy during the 1 1/2 years of observation. By utilizing high resolution-multiparameter flow cytometry for cell analysis and sorting, we have succeeded in isolating and analyzing the population of dormant lymphoma cells. Preliminary studies using DNA dye (Hoechst) and also administration of BrdU indicate that a high proportion of the dormant cells are non-cycling. In the proposed studies, we will determine differences among dormant lymphoma cells, growing lymphoma cells in non-immune mice and growing lymphoma cells in previously dormant mice in an effort to elucidate mechanisms underlying dormancy. Thus, we will extend our studies on cell cycle analysis to determine the history of the dormant cells beginning with their induction from growing BCL1 to their loss of dormancy later in life. We will determine if there are differences in the above three populations with regard to immunophenotype including cytokine receptors, pattern of cytokine production, and the expression of messenger RNA levels of candidate oncogenes that appear to play a role in B cell growth, e.g., myc, Bcl-2, RB and p53. We will determine the in vivo distribution of the dormant cells with regard to organ site and histologic distribution within the spleen. We will determine if the regrowing population which is Id+ is no longer susceptible to the dormancy-inducing effect of anti- Id. Based on our preliminary results, our working hypothesis is: Dormancy is induced by cell cycle arrest of most but not all BCL1 cells due to an Id immune response; this results in down-regulation of growth- promoting oncogenes and up-regulation of suppressor genes; escape from dormancy is due in part to mutations in the subset of dormant BCL1 that is still cycling. The studies to be performed will test these hypotheses and should generate new ones about the mechanisms underlying tumor dormancy.