Lymphoma Cells Associated with Bone Marrow Stromal Cells in Culture Exhibit Altered Growth and Survival

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Abstract
The detection of clonal populations of lymphoma cells in histologically negative bone marrow using culture techniques is a predictor of poor outcome for patients undergoing high dose therapy and autologous transplantation. In positive cultures, lymphoma cells were observed as outgrowths in association with adherent stromal cells, whilst only stromal cells were observed in negative long-term cultures. This study developed an experimental model to further study the interactions occurring between lymphoma cells and stromal cells. Using random dot graticule analysis, 86% and 74%, respectively, of patient lymphoma cells grew in association with stromal cells in leukapheresis and bone marrow harvest cultures with the formation of cobblestone areas at sites of interaction between lymphoma cells and stromal cells. Secondary cultures showed that individual stromal cells were able to support the growth of a small number of lymphoma cells. Coculture of the human lymphoma cell lines with a murine bone marrow stromal cell line, MS-5 also resulted in the formation of cobblestone areas, which corresponded with the suppression of nonadherent cell production by the lymphoma cell lines. Upon interacting with MS-5 cells, the lymphoma cell lines formed pseudopodia and underwent pleiomorphic nuclear changes. Contiguous linear homotypic associations between lymphoma cells were evident, as opposed to focal contacts occurring in the heterotypic interactions between lymphoma cells and MS-5 cells. An increasing proportion of supernatant lymphoma cells underwent apoptosis as time in culture increased. These results demonstrate that bone marrow stromal cells alter the pattern of growth of lymphoma cells and may have an important role in the maintenance of occult lymphoma by inhibiting apoptosis.

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