Selective Inhibition of Bcl6 Could Lead to New Treatment Options for Diffuse Large B-cell Lymphoma

Cancer researchers have demonstrated that it is possible to disable the transcription factor Bcl6 selectively in lymphoma cells without impairing its function in normal cells in the body.

Bcl6 causes the majority of diffuse large B-cell lymphomas (DLBCLs), the most common form of non-Hodgkin lymphoma. Depletion or blockade of Bcl6 potently kills lymphoma cells in tissue culture, and it is therefore a critical therapeutic target. Like many oncogenes and tumor suppressors, Bcl6 is a transcription factor. This protein can interact with several co-repressor complexes to inhibit transcription. The gene for Bcl6 is found to be frequently translocated and highly mutated in DLBCL, and contributes to the pathogenesis of the disease.

Investigators at Weill Cornell Medical College (New York, NY, USA) had previously used an integrated biochemical and computational approach to identify small molecules that could specifically disrupt the activity of Bcl6 by blocking its interaction in the critical BTB groove with its co-repressors BCOR, N-CoR, and SMRT. In the current study, they created a mutated form of Bcl6 that possessed a nonfunctional BTB domain, but was otherwise identical to native Bcl6.

The investigators reported in the March 3, 2013, online edition of the journal Nature Immunology that genetic replacement with mutated Bcl6 that could not bind co-repressors to its BTB domain resulted in disruption of the formation of germinal centers (GCs) and affinity maturation of immunoglobulins due to a defect in the proliferation and survival of B-cells. Germinal centers are sites within lymph nodes (also within lymph nodules in peripheral lymph tissues) where mature B lymphocytes rapidly proliferate, differentiate, mutate their antibodies (through somatic hypermutation), and class switch their antibodies during a normal immune response to an infection.

Loss of function of the BTB domain had no effect on the differentiation and function of follicular helper T-cells or that of other helper T-cell subsets. Bcl6-null mice had a lethal inflammatory phenotype, whereas mice with a mutant BTB domain had normal healthy lives with no inflammation.

"The finding comes as a very welcome surprise," said senior author Dr. Ari Melnick, professor of medicine at 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," said Dr. Melnick. "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. When cells lose control of Bcl6, lymphomas develop in the immune system. Lymphomas are "addicted" to Bcl6, and therefore Bcl6 inhibitors powerfully and quickly destroy lymphoma cells."

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