Findings demonstrate that abnormal expression of the BCL6 gene causes lymphoma

Researchers at Columbia University Medical Center have created the first mouse model that develops a lymphoma the same way that humans do. This advancement has the potential to significantly speed the development of new, improved therapies for diffuse large B cell lymphoma (DLBCL), the most common type of human B cell lymphoma. Human B cell lymphomas cause 85 percent of non-Hodgkin’s lymphomas, the sixth leading cause of cancer deaths in the United States.

The findings also confirm that a mutation in BCL6, the gene most frequently altered in this type of lymphoma, is the first step in its development, though other subsequent mutations also occur. In the study, mice with a mutant form of this gene spontaneously developed this lymphoma.

Cancer researchers have long been hindered by the lack of animal models to recreate both the genetics and biology of DLBCL. They had no way to test, with reliable accuracy, how an investigational therapy would work in humans with this disease. Also, this lack of animal models has slowed understanding of the BCL6 gene and its precise role in tumor development.

Published in the May 2005 issue of Cancer Cell, the study was led by Riccardo Dalla-Favera, M.D., one of the world’s leading cancer geneticists and lymphoma researchers. Dr. Dalla-Favera is the Percy and Joanne Uris Professor of Pathology and Professor of Genetics & Development at the Columbia University College of Physicians and Surgeons. He is also director of the Institute for Cancer Genetics at Columbia University and has been recently appointed director of the Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University and NewYork-Presbyterian/Columbia. The HICCC is one of only three NIH-designated Comprehensive Cancer Centers in New York State.

Dr. Dalla-Favera and his research team genetically engineered mice to produce a mutant BCL6 gene, showing the specific role of this gene in its pathogenesis and displaying most of the critical features of the corresponding human tumor. These findings expand on Dr. Dalla-Favera’s identification of the BCL6 gene in 1994.

“We are very optimistic that this new model for lymphoma will be a catalyst for new therapies for lymphoma; enabling researchers to first test new potential therapies in animals before humans,” said Dr. Dalla-Favera. “We are already using this new model to develop novel therapies targeted to BCL6, so these mice will be valuable in testing these lymphoma-specific compounds.”

This mouse model can also be used to identify the additional genetic alterations that are necessary, in addition to BCL6, to develop diffuse large cell lymphoma.

Additional Columbia investigators associated with the Cancer Cell study include: Drs. Giorgio Cattoretti (Columbia’s Institute for Cancer Genetics and Department of Pathology), Laura Pasqualucci (Institute for Cancer Genetics and Department of Pathology), Subhadra V. Nandula (Department of Pathology), Qiong Shen (Institute for Cancer Genetics), Tongwei Mo (Institute for Cancer Genetics), Vundavalli V. Murty (Institute for Cancer Genetics and Department of Pathology), and Gianna Ballon and Wayne Tam (formerly at the Institute for Cancer Genetics, Columbia University, and presently at the Department of Pathology & Laboratory Medicine, Weill Medical College of Cornell University).