The tumor microenvironment plays a critical role in growth, metastasis, and survival of tumors. Chronic lymphocytic leukemia (CLL) B cells of many patients can rapidly undergo apoptosis in vitro unless co-cultured with accessory cells, which elaborate factors that promote CLL-cell survival. A major type of such accessory cells is nurse-like cells (NLC), which prior studies demonstrated could differentiate from CD14+ blood mononuclear cells when exposed to CLL B cells in vitro, and presumably in vivo. In the absence of CLL cells, blood mononuclear CD14+ cells typically differentiate into macrophages that have a distinctive morphology from that of NLC. We found that, compared with macrophages, NLCs consistently expressed significantly higher levels of B-cell activating factor (BAFF) (n=11), a tumor-necrosis-factor (TNF)-related ligand that promotes survival of B cells, including CLL B cells. To investigate the influence of CLL cells on the differentiation of NLC in vitro, purified CLL B cells or B cells of healthy donors were cultured for 24h to generate conditioned media. When CD14+ blood mononuclear cells of healthy donors were cultured for 7 days in media conditioned by CLL cells, but not in non-conditioned media or in media conditioned by normal B cells, the cells assumed the morphology of NLC, acquired high-level expression of BAFF, and developed an enhanced capacity to support CLL cell survival in vitro. Similar activity was also found in the sera of CLL patients, but not in the sera of healthy control donors. The capacity of either CLL-conditioned media (n=4) or CLL-patient sera (n=9) to induce NLC differentiation leading to increased expression of BAFF was significantly reduced by a decoy receptor for TNF-a, suggesting that TNF-a contributes to the differentiation of NLC in vitro. However, TNF-a alone was not sufficient to induce high-level expression of BAFF on blood mononuclear CD14+ cells, suggesting that additional factors are involved. The results show a previously unrecognized symbiosis between CLL cells and accessory cells in their microenvironment. Because the survival of neoplastic B cells in vivo potentially depends upon NLC found in the lymphoid tissues of patients with CLL, identification of the factor(s) involved in inducing their differentiation could provide a novel target for therapy of patients with this disease.

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