The role of CD1d in survival and growth of hyperdiploid multiple myeloma cells
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Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. It is the second most common hematological malignancy. The cancer is incurable and the overall survival is 5-7 years. MM can be divided into two equally large groups: hyperdiploid and non-hyperdiploid. Ongoing research on MM is mostly based on in vitro studies using human myeloma cell lines (HMCLs). HMCLs from hyperdiploid MM are generally lacking, although this group involves 50% of patients. Since we have been able to establish three hyperdiploid HMCLs, it was important to find factors that enable these cells to grow in vitro. These cells need human serum (HS) to grow in vitro, unlike other HMCLs which are regularly grown in fetal calf serum (FCS). In this study, the main focus was on finding the factor present in HS that has a stimulatory effect on these three hyperdiploid HMCLs. We found that these cells express a cell surface receptor, called CD1d, when cultured in HS. CD1d is normally involved in the presentation of glycolipid antigens to iNKT-cells, which become activated and secrete a large amount of cytokines regulating immune responses. It is thought that CD1d is part of the malignant phenotype, because it is found on the surface of some MM cells, but it is not found on normal plasma cells. We found that CD1d is up-regulated in these three hyperdiploid HMCLs when cultured in HS, and down-regulated when the cells are cultured in FCS. HMCLs and primary myeloma cells were used to find the factor that regulates CD1d expression in HS vs FCS. The expression of CD1d can be regulated by the activation of nuclear receptors, which act as transcription factors that upon ligand binding can activate or inhibit the transcription of genes. In this study, it is shown that CD1d expression can be regulated by a ligand of the retinoic acid nuclear receptor α(RARα). Furthermore, cell proliferation and viability of HMCLs and primary myeloma cells were measured after stimulation of RAR αto investigate whether CD1d up-regulation is related to growth and survival of MM cells. The results show that the increase of cell proliferation and viability correlates to up-regulated CD1d levels in some MM cell. These results indicate that retinoic acid might be the factor present in HS that enables hyperdiploid cells to grow in vitro. However, to draw this conclusion further studies have to be performed.