Leif Bergsagel, M.D., studies the molecular pathogenesis of multiple myeloma.
Multiple myeloma is 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.
In the last few years, 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 and his team 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's 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 colleagues have cloned six translocation breakpoints on 11q13, from 50-300 kb upstream of cyclin D1, associated with the ectopic expression and dysregulation of cyclin D1 mRNA and protein, and translocation breakpoints on 6p21 that dysregulate cyclin D3.
They have also cloned seven translocation breakpoints on 4p16.3, from 50-120 kb upstream of fibroblast growth factor receptor 3 (FGFR3). The t(4;14) is a novel, karyotypically silent translocation associated with the ectopic expression and dysregulation of FGFR3 on der14 mediated by the 3' enhancer of the IgH locus. In addition, there is dysregulation of a novel SET domain protein, which they have called MMSET, mediated by the intronic enhancer on der4.
Dr. Bergsagel has cloned five translocation breakpoints on 16q23 within approximately 500 kb of c-Maf. The t(14;16) is also a novel, karyotypically silent translocation that is associated with the ectopic expression and dysregulation of c-Maf mRNA. In addition, he and his team have cloned translocation breakpoints on 20q11 that result in dysregulation of mafB, highlighting the importance of Maf family members in multiple myeloma.
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 genes in plasma cells.
They are analyzing transgenic mice that express FGFR3, MMSET, c-Maf and cyclin D1 in plasma cells. They're studying how the ectopic expression of cyclin D1, FGFR3 and c-Maf contribute to plasma cell neoplasia and how they may be used as therapeutic targets.
The novel protein MMSET is expressed in developing T cells and germinal center B cells. They have generated a conditional murine allele to study its role in normal lymphocyte development, and they are pursuing a biochemical characterization of its function and protein partners in lymphocyte development.
Dr. Bergsagel and his group are 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.
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 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.
Since the myeloma in this model develops in a mouse with an intact immune system, Dr. Bergsagel and his team are for the first time in a position to assay therapies that act primarily to augment the immune system to eradicate the disease.