Master protein in aggressive lymphomas can be shut down

The powerful master regulatory transcription factor called Bcl6 is key to the survival of a majority of aggressive lymphomas, which arise from the B-cells of the immune system. The protein has long been considered too complex to target with a drug since it is also crucial to the healthy functioning of many immune cells in the body, not just B cells gone bad.

But now, researchers at Weill Cornell Medical College report that it is possible to shut down Bcl6 in the cancer known as diffuse large B-cell lymphoma (DLBCL) while not affecting its vital function in the T cells and macrophages needed to support a healthy immune system. DLBCL is the most common subtype of non-Hodgkin lymphoma, which is the seventh most frequently diagnosed cancer, and many of these patients are resistant to currently available treatments.

"The finding comes as a very welcome surprise," says the study's lead investigator, Ari Melnick, MD, of Weill Cornell Medical College. "This means the drugs we have developed against Bcl6 are more likely to be significantly less toxic and safer for patients with this cancer than we realized.

"Scientists have been searching for the right answer to treat this difficult lymphoma, which, after initial treatment, can be at high risk of relapse and resistant to current therapies," Melnick says. "Believing that Bcl6 could not be targeted, some researchers have been testing alternative therapeutic approaches. This study strongly supports the notion of using Bcl6-targeting drugs."

The discovery that a master regulatory protein can be targeted offers implications beyond just treating DLBCL. Bcl6 also plays a key role in the most aggressive form of acute leukemia and in certain solid tumors.

The big surprise in the current study is that rather than functioning as a single molecular machine, Bcl6 instead seems to function more like a Swiss Army knife, using different tools to control different cell types. This multifunction paradigm could represent a general model for the functioning of other master regulatory transcription factors.

"In this analogy, the Swiss Army knife, or transcription factor, keeps most of its tools folded, opening only the one it needs in any given cell type," said Melnick. "For B cells, it might open and use the knife tool; for T cells, the cork screw; for macrophages, the scissors. The amazing thing from a medical standpoint is that this means that you only need to prevent the master regulator from using certain tools to treat cancer. You don't need to eliminate the whole knife," he says. "In fact, we show that taking out the whole knife is harmful since the transcription factor has many other vital functions that other cells in the body need."

This study was published in Nature Immunology (2013; doi:10.1038/ni.2543).

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