The laboratory of Diane F. Jelinek, Ph.D., studies normal human B cell (lymphocyte) and plasma cell biology as well as several human B cell cancers. Dr. Jelinek and her team research how normal human B cells survive, increase in number in response to various signals, and differentiate into either memory B cells or antibody-secreting plasma cells.
These studies allow her team to acquire a better understanding of the molecular changes that cause various B cell cancers and diseases, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma and primary amyloidosis.
Normal B cell and plasma cell biology. Dr. Jelinek and her colleagues study interactions between B cells and innate immune cells as well as several important cell surface receptors, including the B cell antigen receptor, toll-like receptors, cytokine receptors and the receptor for CD40 ligand, a molecule expressed on T lymphocytes that is necessary to activate some B cells. Tools in the laboratory allow them to engage each of these receptors and then assess relevant biological changes.
For example, it is known that during an immune response, B cells are induced to express a highly mutagenic enzyme called activation-induced cytidine deaminase (AID). Although AID is needed to increase the effectiveness of plasma cell-derived secreted antibodies, it also has the potential to cause mutations in other genes expressed by B cells. Dr. Jelinek's laboratory is exploring what role AID might play in the initiation of mature B cell malignancies and how this may further change with age. Lastly, Dr. Jelinek and her team are using next-generation sequencing focused specifically on antibody genes so that they can deeply probe the antibody repertoire in healthy people and those with B cell cancers.
Chronic lymphocytic leukemia (CLL). CLL is the most common adult-onset B cell cancer. As a result of still poorly understood mechanisms, a single B cell acquires a genetic abnormality (or abnormalities) that leads to proliferation and massive accumulation of leukemic B cells that reside in blood, lymph nodes and bone marrow. CLL is a very heterogeneous disease, with some patients surviving only a very short time and others surviving for considerably longer.
Dr. Jelinek and her group believe that molecular features of the CLL B cell antigen receptor play a key role in this heterogeneity; because of this, they have characterized this receptor in more than 2,000 patients. They have also determined the broad gene expression profile of CLL cells and compared this with normal blood B cells, allowing them to identify and then study in detail specific differentially expressed genes in CLL cells. She and her colleagues are also studying how they can alter the transformation state of CLL cells using biological agents that cause transition into a nonproliferative state.
Multiple myeloma (MM) and its premalignant precursor conditions. In normal people, 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, and Dr. Jelinek's laboratory is broadly interested in understanding the regulation of tumor cell growth control in this devastating disease. In addition, the laboratory is interested in the specific genetic and epigenetic events that occur when a patient with a MM precursor condition begins to progress into symptomatic MM.
Studies are focused on freshly isolated patient tumor cells, as well as a panel of human MM cell lines that were established in the laboratory. Current studies focus on molecular properties of the tumor cell B cell antigen receptor, acquisition of an interesting cell surface receptor (CD147) that might explain a variety of disease features, and metabolic changes acquired in the tumor cells.
- Primary amyloidosis (AL) and other antibody-secreting disorders. Patients with AL have an expanded clonal population of plasma cells that cause disease because of unique properties displayed by the antibodies they secrete. These altered antibodies cause life-threatening organ deposits. Dr. Jelinek and her team are interested in better understanding the biology of the amyloid-producing plasma cells. They have also begun to study IgG4-related disease, another pathologic condition that results in disease-causing accumulation of IgG4-producing plasma cells.
Significance to patient care
The work of Dr. Jelinek and her team addresses diseases that thus far do not have cures. Her team's strategy to exploit normal B cell and plasma cell biology as a means to identify cancer-relevant genetic changes holds promise to identify new targets for therapeutic intervention.
- Gene and Mary Lou Kurtz Professor of Multiple Myeloma Research, 2008