Researchers have discovered how an experimental drug is capable of completely eradicating human lymphoma in mice after just five doses. The study, led by researchers at Weill Cornell Medical College, sets the stage for testing the drug in clinical trials of diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma.
In the journal Cell Reports, published online, the scientists describe how the powerful master regulatory transcription factor Bcl6 regulates the genome, ensuring that aggressive lymphomas survive and thrive. They also show how the Bcl6 inhibitor, developed at Weill Cornell, effectively gums up the protein, stopping it from working.
In a study published in March in Nature Immunology, Dr. Melnick and his team reported that it is possible to shut down Bcl6 in DLBCL without affecting its vital role in the T cells and macrophages needed to support a healthy immune system. The protein haslong been considered too complex to target with a drug as it also is crucial to proper function of many immune system cells, not just B cells gone bad.
The latest study was designed to understand exactly how Bcl6 promotes DLBCL.
Transcription factors are responsible for either inhibiting or promoting the expression of genes, and master regulatory transcription factors are like transcription factors on steroids: their actions regulate thousands of genes in different kinds of cells. Bcl6 can control the type of immune cell that develops in the bone marrow -- pushing them to become B cells, T cells, or macrophages -- and it has a primary role in the developmental phase of B cells, during which they generate specific antibodies against pathogens.
Bcl6 also has a second, independent function that Melnick says acts like a switch on railroad track that routes a train in one direction or another. One track is needed when antibodies are required for an immune response, while the other keeps B cells in a constant state of division.
Source: Weill Cornell Medical College