Effects of bone morphogenetic proteins, hepatocyte growthfactor and interleukin-21 in multiple myeloma

Abstract

The studies presented in this thesis answer some questions, but also raise new questions which should be explored in future studies. The bone marrow microenvironment is a complex system, and is difficult to study in vitro. Thus, the effects of IL-21, c-met inhibition and BMPs should be explored in a MM mouse model. The BMPs are unique among cytokines in their ability to induce apoptosis and inhibit growth of primary MM cells as well as MM cell lines. In addition, they stimulate bone formation and appear as ideal agents against MM. Our discovery in paper V that one tumor suppressor, BMP-4, is dependent on the activity of another tumor suppressor, p53, should be further explored. For instance, which kinase is responsible for p53 phosphorylation? Are other proteins besides p53 important for BMP-induced growth inhibition? What is the role of BMPs in normal B- and plasma cell development?

At our research group meetings, there are rare occations when we are tired of discussing research results. We talk about soccer instead, but of course from a scientific point of view. There seems to be a clustering of skilled soccer players within certain families, but is it caused by their genes or their environment? The discussion is far from closed, but our conclusion so far is that both aspects are important. I mention this to draw the parallell to myeloma cells. The behavior of MM cells is, and I believe more than other cancer cells, dependent on both genes (e.g. chromosomal translocations, oncogenes, and tumor suppressor genes) and the environment (e.g. bone marrow cells, adhesion molecules and cytokines). We have chosen to focus on the bone marrow environment in our research. Through studies of cellular and molecular properties of the MM cells in their microenvironment, we want to provide a basis for rational strategies for treatment of MM