DORMANT LYMPHOMA CELLS (DLC) FROM MICE

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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.