Molecular and cellular immunology; tumor biology

Our research centers on the study of normal and malignant human B lymphocytes. The tools of molecular biology are used to understand the means by which various stimuli elicit their cellular effects on normal B lymphocytes and how these pathways become altered during malignant transformation. One area of research is focused on dissecting cytokine-mediated signaling pathways in normal vs. transformed B cells. A second area is concerned with the identification and study of genes that are differentially expressed in normal vs. malignant B cells. A third major area of research is directed at increasing our understanding of the mechanisms underlying differentiation blockades in B cell malignancies.

Specific Research Topics

Characterization of signaling events that occur during normal B lymphocyte differentiation into immunoglobulin secreting cells. The induction of an immunoglobulin response is a complex process that involves the coordination of two types of signals. The first type of signal is mediated by either binding of antigen via membrane immunoglobulin or signaling via specific cell-cell interaction molecules. After B lymphocytes are activated by the first signal, the second type of signal is mediated by a variety of soluble protein molecules called cytokines. During a normal B cell immune response, B cell proliferation is an integral aspect of B cell differentiation into immunoglobulin secreting plasma cells. However, terminal differentiation of B cells into plasma cells typically coincident with loss of growth potential. Our work has shown that the cellular signals required for proliferation are distinct from those required for differentiation. Current research focuses on further delineation of the signals required for B lymphocyte growth versus the signals required for B lymphocyte differentiation. To facilitate our studies of the various stages of B cell maturation, we are also studying two human B cell malignancies that result from the malignant transformation of B cells at two different stages of development.

B cell chronic lymphocytic leukemia (B-CLL). B-CLL is characterized by the massive accumulation in blood of monoclonal B cells with the appearance of small mature B lymphocytes. The vast majority of these cells are in the G0 phase of the cell cycle, are typically unresponsive to mitogenic stimulation, and exhibit defects in cell death. The failure of these cells to undergo proper programmed cell death may in part underlie the accumulation of the leukemic B cells. Despite the relatively uniform morphology exhibited by B-CLL leukemic cells, it is also clear that B-CLL is a very heterogeneous disease, with some patients surviving only a very short time following diagnosis and others surviving for considerably longer periods of time. Our work on B-CLL is an integral component of the B-Chronic Lymphocytic Leukemia Research Program that is directed by Dr. Neil Kay. Our studies are broadly focused on several areas of interest: 1) Can we identify biological and molecular parameters that underlie the differential patterns of disease course? 2) Does the amount of somatic mutation in the immunoglobulin variable region gene serve as a useful prognostic factor, and if so, why? 3) What are the gene expression profiles of B-CLL cells and how do they differ from normal counterpart B lymphocytes? and 4) What are the molecular mechanisms that underlie the failure of B-CLL cells to differentiate into immunoglobulin secreting cells?

Multiple myeloma (MM). In normal individuals, plasma cells do not proliferate and therefore account for only a very small percentage of the cells found in bone marrow. By contrast, myeloma cells retain proliferative potential (interleukin 6 is an important growth factor) and the laboratory is broadly interested in understanding the regulation of tumor cell growth control in this disease. Study is focused on freshly isolated patient tumor cells, as well as a panel of human multiple myeloma cells lines that were established in the laboratory. There are several specific projects that are currently ongoing in the laboratory: 1) How does IL-6 signal transduction in myeloma cells differ from IL-6 signaling of normal plasma cells and what genes are IL-6-responsive in myeloma cells? 2) What is the role of anomalous receptor cross-talk in tumor cell growth control? 3) What are the gene expression profiles of myeloma cells and can this information be used to better define subsets of myeloma? and 4) By what molecular mechanism does the IL-6 receptor and the receptor for insulin-like growth factor become overexpressed in myeloma cells and what is the role of this event in tumorigenesis? Because of the availability of the myeloma cell lines, we are able to address these questions utilizing a variety of methodologies, including cellular immunology, protein biochemistry, and molecular biology.