Bcl-6 oncogene - genetic target for lymphoma treatment

Dec 5 2004

Results from a pre-clinical study show that the gene designated Bcl-6 is an oncogene -- that is, one with the potential to cause a normal cell to become cancerous -- but that certain peptide inhibitors can in effect inactivate it, according to a study to be presented today during the 46th Annual Meeting of the American Society of Hematology (ASH).

Every year, more than 50,000 Americans are diagnosed with non-Hodgkin's lymphoma. Diffuse large B-cell lymphoma (DLBCL) -- the most common form of non-Hodgkin's lymphoma and the focus of this study -- comprises about a third of those cases.

The Bcl-6 gene codes for a special protein, called a transcriptional repressor, which is a master regulator required for a specific stage in the life cycle of B-cells. Normally, B-cells are in charge of making the antibodies that protect the organism from infection. However, B-cell tumors like DLBCL arise when mutations occur, leading to the inappropriate expression of Bcl-6. At least 50 percent of these patients ultimately succumb to the illness in spite of aggressive chemotherapy regimens and stem cell transplantation.

Bcl-6 causes cancer by silencing other genes throughout the genome. Researchers from the Albert Einstein College of Medicine, the Mount Sinai School of Medicine, and the Ontario Cancer Institute engineered special BTB peptide inhibitors (BPI) that bind with very high specificity to Bcl-6 and block its ability to silence critical genes that need to be off for tumors to survive.

In the study, DLBCL cells were exposed to BPI. Remarkably, practically all of the DLBCL cells with active Bcl-6 genes underwent severe growth suppression, cell cycle arrest, and cell destruction. Additionally, BPI completely blocked the actions of Bcl-6 in an animal model of Bcl-6 activity, without harming any other organ and without any detectable side effects.

According to Ari Melnick, M.D., Assistant Professor at the Albert Einstein College of Medicine and lead author of the study, "These exciting results indicate that Bcl-6 is a new specific therapeutic target for diffuse large B-cell lymphoma and that BPI is a potent, highly specific, and non-toxic treatment to address this target."

http://www.hematology.org/