Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING
JIB

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

By BiotechDaily International staff writers
Posted on 12 Mar 2013
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."

Related Links:
Weill Cornell Medical College


comments powered by Disqus

Channels

Drug Discovery

view channel
Image: The European Commission has approved the use of Avastin combined with chemotherapy as a treatment for women with recurrent ovarian cancer (Photo courtesy of Genentech).

Drug for Treatment of Platinum Resistant Recurrent Ovarian Cancer Approved for Use in Europe

For the first time in more than 15 years the European Commission (EC) has approved a new therapeutic option for the most difficult to treat form of ovarian cancer. Ovarian cancer causes more deaths... Read more

Therapeutics

view channel
Image: This type of electronic pacemaker could become obsolete if induction of biological pacemaker cells by gene therapy proves successful (Photo courtesy of Wikimedia Commons).

Gene Therapy Induces Functional Pacemaker Cells in Pig Heart Failure Model

Cardiovascular disease researchers working with a porcine heart failure model have demonstrated the practicality of using gene therapy to replace implanted electronic pacemakers to regulate heartbeat.... Read more

Lab Technologies

view channel
Image: The DrySyn MULTI converts any standard hotplate stirrer into a high performance reaction block (Photo courtesy of Asynt).

New Reaction Vessel Heating System Is Cleaner and Safer

Biotech and other life science researchers can create a safer, cleaner, and more efficient working environment in their laboratories by switching from oil bath-based heating of reaction vessels to a new... Read more

Business

view channel

Global Computational Biology Sector Expected to Reach over USD 4 Billion by 2020

The global market for computational biology is expected to reach USD 4.285 billion by 2020 growing at a compound annual growth rate (CAGR) of 21.1%, according to new market research. Steady surge in the usage and application of computational biology for bioinformatics R&D programs designed for sequencing genomes... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.