SUMMARY
Leif Bergsagel, M.D., studies the molecular pathogenesis of multiple myeloma, a tumor of mature, isotype-switched plasma cells. It is a uniformly fatal malignancy that is frequently preceded by a common (1 percent of adults), benign preclinical phase known as monoclonal gammopathy of undetermined significance (MGUS).
Dr. Bergsagel's laboratory is focused on understanding the molecular events that lead to the development of MGUS and its progression to multiple myeloma.
Focus areas
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Association of chromosome translocation and multiple myeloma. Dr. Bergsagel and his team have determined that multiple myeloma is characterized by recurrent chromosome translocations to the immunoglobulin heavy chain gene on 14q32. They have cloned more than 35 translocation breakpoints and identified five frequent translocation partners that are present in almost one-half of patients with multiple myeloma.
The translocations appear to be initiating events in the tumorigenic process and are present in MGUS. From a detailed analysis of the breakpoints, it is clear that the translocations are frequently mediated by aberrant activity of B cell-specific mechanisms: somatic hypermutation and isotype switch recombination.
Dr. Bergsagel and his team are now working to identify and clone various translocation breakpoints in order to clarify their roles in the development of multiple myeloma. They are also continuing their analysis and cloning of novel translocation breakpoints and oncogenes, as well as using microarray gene expression analysis to identify other molecular targets in myeloma.
- Ectopic gene expression. Dr. Bergsagel and his team are now using murine and in vitro models to study ectopic gene expression mediated by somatic hypermutation and isotype switch recombination, as well as to develop faithful mouse models of myeloma. They have generated several different transgenic vectors, both conventionally and using bacterial artificial chromosomes, to ectopically express specific genes in plasma cells. They are studying how the ectopic expression of these genes contributes to plasma cell neoplasia and how the genes may be used as therapeutic targets. A current focus is on the MYC oncogene that appears in some patients to cause the progression of MGUS to myeloma.
Significance to patient care
The research of Dr. Bergsagel and his colleagues has identified important subtypes of multiple myeloma that respond differently to treatment, are associated with different survival rates and form the basis for a risk-adapted approach to therapy.
Using insights gained from an understanding of the genetic events that lead to the development of multiple myeloma, Dr. Bergsagel and his team have generated a mouse model of the disease. They are using this model to screen novel agents for their anti-myeloma activity.
Professional highlights
- Member, Association of American Physicians, 2010-present
- Member, Basic Mechanisms of Cancer Therapeutics Study Section, National Institutes of Health, 2009-present
- Member, American Society for Clinical Investigation, 2004-present
- Bertha A. Bouroncle lectureship, Ohio State University Medical Center, 2013
- David A. Galton lectureship, Hammersmith Hospital, London, 2012
- David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research II, 2011
- Daniel E. Bergsagel visiting professorship, Ontario Cancer Institute, 2010
- Robert A. Kyle Mayo Clinic Distinguished Investigator Award, 2009