SUMMARY
Leif Bergsagel, M.D., studies the molecular pathogenesis of multiple myeloma, which is a tumor of mature, isotype-switched plasma cells. Multiple myeloma is a treatable but incurable malignancy. In 1% of adults, a benign preclinical phase known as monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma.
Dr. Bergsagel's laboratory work focuses on understanding the molecular events that lead to the development of MGUS and its progression to multiple myeloma.
Focus areas
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. He has cloned more than 35 translocation breakpoints and identified five frequent translocation partners that are present in almost one-half of people 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. These aberrant B cell-specific mechanisms are somatic hypermutation and isotype switched recombinations.
Dr. Bergsagel and his team are identifying and cloning various translocation breakpoints in order to clarify the roles that translocation breakpoints have in the development of multiple myeloma. He is analyzing and cloning new 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 using murine and in vitro models to study ectopic gene expressions mediated by somatic hypermutations and isotype switched recombinations. He also is developing faithful mouse models of myeloma. Dr. Bergsagel has generated several different transgenic vectors, both conventionally and using bacterial artificial chromosomes, to ectopically express specific genes in plasma cells. He researches 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 to cause the progression of MGUS to myeloma in some people.
- Developmental therapeutics. Dr. Bergsagel and his team are working to bring new therapeutic approaches, including small molecules, immunotherapy and their combination, to the treatment of individuals with multiple myeloma. The team performs preclinical studies to determine efficacy and early-stage clinical trials for people with relapsed and refractory multiple myeloma.
Significance to patient care
The research of Dr. Bergsagel and his colleagues 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 mouse model to screen new agents for antimyeloma activity.
Professional highlights
- Member, Association of American Physicians, 2010-present.
- Member, American Society for Clinical Investigation, 2004-present.
- Bertha A. Bouroncle lectureship, Ohio State University Medical Center, 2013.
- Principal investigator, SPORE in Myeloma, Project 4, funded by National Cancer Institute, Mayo Clinic:
2008-2013.
2004-2008.
- 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, Mayo Clinic, 2009.