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
Phone:
301-594-6049
Running Title of Program:
The role of Fc-receptor like proteins in regulating B cell function.
Research Project Summary:
Fc-receptor like (FCRL) comprise a family of six recently identified membrane proteins implicated in B cell tumor development and autoimmunity. Due to their restricted expression on specific subpopulations of B cells, FCRL are also potential new tumor markers and candidate targets of tumor immunotherapy. Our laboratory has been investigating the regulation of FCRL gene expression and the functional roles of FCRL proteins. One current focus is to identify onco-viruses and oncogenes that perturb FCRL gene expression and study the functional outcome. Better understanding of the functions and transcriptional regulation of FCRL will help define the role of FCRL in tumor formation and progression.
Proposed Project for IOTF Fellow:
The fellow will pursue regulation of FCRL 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 FCRL, FCRL5, encoded on chromosome 1q21, through the host DNA-binding protein CBF1. In Burkitt’s lymphoma cell lines with chromosome 1q21 abnormalities FCRL5 expression is deregulated, implicating FCRL5 in lymphomagenesis. EBNA2-induced expression of FCRL5 may contribute to the development of Epstein-Barr virus associated tumors, including Burkitt’s lymphoma. Our novel findings implicating CBF1 in the induction of FCRL5 expression raise the possibility of other CBF1 dependent transcription factors regulating the FCRL5 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. The functional impact of elevated B cell FCRL5 expression will be evaluated.
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.
Selected References:
Mohan, J., Dement-Brown, J., Maier, S., Ise, T., Kempkes, B. and Tolnay, M. (2006) Epstein-Barr virus nuclear antigen 2 induces FCRL5 expression through CBF1. Blood, 107:4433.
