DORMANT LYMPHOMA CELLS FROM MICE

BCL 1是一种高度可移植的鼠B细胞淋巴瘤， 通常在6-8周内对小鼠致死。 我们开发了两种模型， BCL 1小鼠的肿瘤休眠：BALB/c小鼠预先免疫接种 BCL 1-免疫球蛋白或被动给予鼠多克隆抗BCL 1抗体， SCID小鼠中的独特型。 在这两种模型中，大多数小鼠具有1-3个 x 106个休眠的BCL 1细胞在他们的脾脏中存活数月。 有一个 在一年半的时间里， 观察. 利用高分辨率多参数流式细胞术 对于细胞分析和分选，我们已经成功地分离和 分析休眠淋巴瘤细胞的数量 初步研究 使用DNA染料（Hoechst）和BrdU的施用表明， 高比例的休眠小区是非循环的。 拟议 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。 以前休眠的小鼠，以阐明潜在的机制， 休眠 因此，我们将把我们对细胞周期分析的研究扩展到 确定休眠细胞从诱导开始的历史 从生长BCL 1到生命后期休眠的丧失。 我们将 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， 细胞因子的产生和信使RNA水平的表达， 似乎在B细胞生长中起作用的候选癌基因，例如， myc、Bcl-2、RB和p53。 我们将确定在体内分布的 休眠细胞的器官部位和组织学分布 在脾脏内。 我们将确定， 是Id+不再对抗-Id的休眠诱导作用敏感。 ID. 根据我们的初步结果，我们的工作假设是： 休眠是由大多数但不是所有BCL 1细胞的细胞周期停滞诱导的 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 休眠部分是由于休眠BCL 1亚群中的突变， 还在骑车 将要进行的研究将检验这些假设 并应该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.