Joint Fellowship Training Program
Mentor:
Mate Tolnay, Ph.D.
Organizational Affiliation and Position:
Principal Investigator, Laboratory of Molecular and Developmental Immunology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center of Drug Evaluation and Research, Food and Drug Administration
Email:
mate.tolnay@fda.hhs.gov
Telephone:
301-827-0775
Running Title of Program:
The role of Fc-receptor homologs in regulating B cell function.
Research Project Summary (if applicable):
Fc-receptor homologs (FcRH) comprise a family of six recently identified membrane proteins implicated in B cell tumor development. Due to their restricted expression on specific subpopulations of B cells, FcRH are also potential new tumor markers and candidate targets of tumor immunotherapy. Our laboratory has been investigating the regulation of FcRH gene expression and the functional roles of FcRH proteins. Our current focus is to identify onco-viruses and oncogenes that perturb FcRH gene expression. Better understanding of the functions and transcriptional regulation of FcRH will help define the role of FcRH in tumor formation and progression.
Proposed Project for IOTF Fellow:
The fellow will pursue regulation of FcRH expression by Epstein-Barr virus and host oncogenes, and its implications in tumor development. We have shown that Epstein-Barr virus nuclear antigen 2 (EBNA2) induces the expression of one of the FcRH, FcRH5, encoded on chromosome 1q21, through the host DNA-binding protein CBF1. In Burkitt's lymphoma cell lines with chromosome 1q21 abnormalities FcRH5 expression is deregulated, implicating FcRH5 in lymphomagenesis. EBNA2-induced expression of FcRH5 may contribute to the development of Epstein-Barr virus associated tumors, including Burkitt's lymphoma. Our novel findings implicating CBF1 in the induction of FcRH5 expression raise the possibility of other CBF1 dependent transcription factors regulating the FcRH5 gene. Activated Notch, a cellular protein, uses CBF1 to target responsive promoters through mechanisms similar to those used by EBNA2. Notch2 is overexpressed in B-cell chronic lymphocytic leukemia cells, suggesting that alterations of the Notch-CBF1 pathway significantly impact malignant transformation. Results of this work can provide insights into mechanisms that lead to deregulated FcRH expression in tumor cells, and elucidate the specific contributions of viral proteins and host oncogenes.
The position is located on the NIH campus.
Regulatory Activity:
The Division of Monoclonal Antibodies regulates therapeutic and diagnostic monoclonal antibodies. The fellow will perform regulatory review of new oncology products as part of an inter-disciplinary team to assess the potential efficacy and safety of the drugs, and communicate directly with product Sponsors.
Reference(s):
Mohan, J., Dement-Brown, J., Maier, S., Ise, T., Kempkes, B. and Tolnay, M. (2006) Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1. Blood (in press)
