The role of bone morphogenetic protein-9 in multiple myeloma

Multiple myeloma (MM) is a malignancy of antibody producing plasma cells located in the bone marrow. MM is also called bone marrow cancer and is the second most common hematologic cancer. The exact cause for this type of cancer is still unknown and the disease is today generally thought to be incurable. One hallmark of MM is the degradation of bone. Bone morphogenetic proteins (BMP) are a group of signaling molecules that have multiple roles in normal and malignant cells. BMPs regulate growth, differentiation and apoptosis in myeloma cells, but also have a role in the induction of bones. This means that BMPs have the potential to inhibit the growth of cancer cells and reduce the degradation of bones. In this thesis BMP-9 was studied by looking at how it affects apoptosis and proliferation in different types of human myeloma cell lines (hMCLs). Experiments were also performed to see if any of the common BMP antagonists had an effect on this protein. Efforts were also made to identify by which receptors BMP-9 signals in myeloma cells and which downstream signaling pathways are activated. It was found that BMP-9 induced apoptosis and/or inhibited proliferation in several hMCLs. The SMAD pathway was activated by BMP-9 in myeloma cells, and BMP-9 most likely uses ALK-2 as Type I receptor and ACVR2A or ACVR2B as Type II receptor in these cells. The antagonists CHL-1 and Tsg, the Type III receptor endoglin and the SMAD inhibitor DMH1 were found to interfere with BMP-9 signaling. Another interesting discovery was that CpG-ODN did not have the same inhibitory effect on BMP-9 as has been shown on other BMPs. Further experiments have to be done to investigate what makes BMP-9 different from other BMPs in this regard