EBV Role In Blood Cancers

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Mechanism For Epstein-Barr Virus Protein's Role In Blood Cancers

Discovered

Category: Lymphoma/Leukemia News

Article Date: 26 Dec 2005

Earlier this year, researchers at the University of Pennsylvania

School of Medicine identified a link between a critical cancer

pathway and an Epstein-Barr Virus (EBV) protein known to be expressed

in a number of EBV-associated cancers. Their findings demonstrated a

new mechanism by which EBV can transform human B cells from the

immune system into cancerous cells, which can lead to B-cell

lymphomas. Now, they have found that the viral protein--called EBNA3C

(for EBV nuclear antigen)--mediates the degradation of the

retinoblastoma protein, an important molecular brake for cell

proliferation.

Erle S. on, PhD, an Associate Professor of Microbiology who

leads the Tumor Virology Program at Penn's Abramson Cancer Center,

and MD/PhD student Knight, published their results last week in

the Proceedings of the National Academy of Sciences.

The retinoblastoma protein (Rb) is a major regulator of several genes

in charge of cell proliferation and cell-cycle regulation. In the

nucleus, Rb normally binds to E2F, turning off genes involved with

cell proliferation. Using human cell cultures infected with the

Epstein-Barr virus, the investigators found that EBNA3C recruits a

group of molecules called the SCF complex, which attaches ubiquitin

to Rb. This inadvertently tags Rb for degradation by the proteosome

machinery, the cell's recycling plant. With Rb out of the way, the

cell now reproduces uncontrollably.

" It's as simple as that, but it's a major mystery solved that many

researchers have been working on for at least 15 years, " says

on.

EBV, a member of the herpesvirus family and one of the most common

human viruses, plays a role in cancers such as lymphoproliferative

diseases in transplant or AIDS patients, Burkitt's lymphoma,

Hodgkin's lymphoma, and nasopharyngeal carcinoma, and also causes the

well-known disease infectious mononucleosis. As many as 95 percent of

adults 20 years and older have been infected with EBV, but show no

symptoms.

Now, the researchers are in the process of blocking the molecular

signals caused by EBNA3C's presence in B cells. This points the way

to a possible drug for EBV-related cancers. " Stopping this step in

the life cycle of EBV could be a major potential target for the

development of therapeutics for treating EBV-related B cell

lymphomas, " says on. " This is especially important because a

large percentage of patients are non-responsive to the current

frontline drug for treating B cell lymphoma, a CD20 monoclonal

antibody. " The researchers surmise that the first use of future

therapies from these studies could be in lymphoproliferative disease

in transplant and immunocompromised patients.

This research was funded by the National Institutes of Health and the

Leukemia and Lymophoma Society of America. Nikhil Sharma, a student

from Cherokee High School, New Jersey and volunteer at Penn at the

time of the study, and now an undergraduate at s Hopkins

University, was also a co-investigator in this study.

This release can also be found at: http://www.uphs.upenn.edu/news.