Working with a master

Researchers uncover new characteristics regarding a master regulatory transcription factor with significant inhibitory potential in lymphoma

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NEW YORK—Working with and against the human immune system—inthe cases of immunotherapies and immunological diseases—has long beenrecognized as a delicate balance. Researchers continue to seek therapies thatcan activate the immune system to target malignancies such as cancer cellswithout endangering healthy cells, or dial back the immune system's erroneousattack on healthy cells without crippling immune response as a whole—manydiseases require therapeutics that step carefully, as it were.
Diffuse large B-cell lymphoma (DLBCL) is one such target. Inthis particular cancer, the lymphomas' survival hinges on Bc16, a masterregulatory transcription factor that also plays a pivotal role in the healthyfunctioning of many immune cells. Due to its importance, Bc16 has generallybeen avoided as being too complex to target; while inhibiting Bc16 could serveto cripple the lymphomas, it also runs the risk of saddling patients withsystemic inflammation and atherosclerosis. A team of researchers at WeillCornell Medical College, however, have completed a study that reveals moreabout Bc16's functions, the risks associated with Bc16 inhibition and a way toshut down Bc16 in DLBCL that doesn't affect its function in T cells andmacrophages.
Transcription factors' duties consist of either inhibitingor promoting the expression of genes, while master regulatory transcriptionfactors such as Bc16 orchestrate the regulation of thousands of genes in a widerange of cells, making use of a variety of tools to control different celltypes. Bc16 controls the type of immune cells that develops in bonemarrow—which plays several roles in the development of B cells, T cells andmacrophages, among others—and can also enable B cells to generate specificantibodies against pathogens. Dr. Ari Melnick, the study's lead investigator,explained Bc16's versatility by likening the transcription factor to a SwissArmy knife.
"In this analogy, the Swiss Army knife, or transcriptionfactor, keeps most of its tools folded, opening only the one it needs in anygiven cell type. For B cells, it might open and use the knife tool; for Tcells, the cork screw; for macrophages, the scissors. The amazing thing from amedical standpoint is that this means that you only need to prevent the masterregulator from using certain tools to treat cancer," said Melnick in a pressrelease. "You don't need to eliminate the whole knife. In fact, we show thattaking out the whole knife is harmful since the transcription factor has manyother vital functions that other cells in the body need."
The findings came about from preclinical testing of twoBc16-targeting agents developed Melnick and his team to treat DLBCLs: RI-BPI, apeptide mimic, and the small-molecule agent 79-6. Melnick is ahematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell MedicalCenter, as well as Gebroe Family Professor of Hematology/Oncology and directorof the Raymond and Beverly Sackler Center for Biomedical and Physical Sciencesat Weill Cornell.
DLBCL is the most common subtype of non-Hodgkin's lymphoma,and the seventh most frequently diagnosed type of cancer, and with the NationalCancer Institute predicting 69,740 new cases of non-Hodgkin lymphoma in 2013 inthe United States alone (and 19,020 deaths), new avenues for possibletherapeutic approaches are welcome.
"Scientists have been searching for the right answer totreat this difficult lymphoma, which, after initial treatment, can be at highrisk of relapse and resistant to current therapies," Melnick said in a pressrelease. "Believing that Bcl6 could not be targeted, some researchers have beentesting alternative therapeutic approaches. This study strongly supports thenotion of using Bcl6-targeting drugs."
This discovery, Melnick noted, "means the drugs we havedeveloped against Bcl6 are more likely to be significantly less toxic and saferfor patients with this cancer than we realized."
In addition, it could also lead to new work in otherdiseases as well, as recent studies—from Melnick, amongst others—have shownthat Bc16 also plays a role in some solid tumors and the most aggressive formsof acute leukemia. The revelation of Bc16 as having numerous functions that canbe applied separately could allow researchers to target or inhibit certain ofits "tools" depending on the disease and the desired result.
This study is the latest research from Weill Cornell intoDLBCL this year. Melnick and his team announced the publishing of another studyin January in Cancer Cell thatdetailed their work with MALT1, a protein that drives cancer cell growth inactivated B cell-DLBCL.
Co-authorsfor this study, "Lineage-specific functions of Bcl-6 in immunity andinflammation are mediated by distinct biochemical mechanisms," include Drs.Chuanxin Huang and Katerina Chatzi from the Division of Hematology and Oncologyat Weill Cornell Medical College. The study appeared in Nature Immunology.

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