Interleukin-6 signal transduction in multiple myeloma

Interleukin-6 is a pleiotropic cytokine that plays an important role in Multiple Myeloma. It also influences the therapeutic response of the myeloma. Myeloma cells reside and accumulate in the bone marrow microenvironment; a rich source of growth factors and cytokines important for cellular interactions. Patients with multiple myeloma often have elevated interleukin-6 levels. Such levels can influence myeloma cell survival and growth. To further understand the role of interleukin-6 in multiple myeloma, this thesis addresses the role of the bone marrow stromal environment in vitro on myeloma therapeutic responses and the potential deregulation in IL-6 signaling in myeloma.; To address the role of the bone marrow microenvironment in the therapeutic response of myeloma cells, an in vitro co-culture system was established. Bone marrow stromal cells were cultured with myeloma cells and the effects of the therapeutic treatments were assessed by apoptotic assay and cell cycle profile. Interleukin-6 from the bone marrow stromal cells was found to play a critical role in stromal related protection of myeloma cells. It was also found to contribute significantly to enhancing the sensitivity of myeloma cells to DNA damaging agent.; To further investigate the mechanisms behind the unusual proliferative response of malignant plasma cells, I have studied myeloma and lymphoblastoid cell lines that mimic IL-6-induced B-cell terminal differentiation. Prolonged activation of STAT3 was observed in myeloma cell lines and patient samples. It correlated with the increased expression of Bcl-X_L and c-myc, in myeloma cell line. Defect in protein tyrosine phosphatase SHP-2 was also observed in myeloma cell lines. Phosphatase inhibitor studies suggested a negative role of the phosphatases in STAT3 activation.; Since myeloma has been suggested as a proliferative disease of plasma cells, I have examined a critical transcription repressor (B-Lymphocyte Induced Maturation Protein-1) in the terminal developmental stage of B-cells. Blimp-1 is shown to be the master regulator of terminal differentiation of B-cells. Defect in Blimp-1 may interfere with cell cycle progression and cell survival in terminally differentiated B-cells. A defect in Blimp-1 promoter DNA binding was observed in myeloma cell lines but not in interleukin-6 induced terminal differentiating B-cell lines.