Sunnybrook Health Sciences Centre
2075 Bayview Avenue, T2 047
Toronto, Ontario M4N 3M5
Phone: (416) 667-2430
Lab Phone: (416) 581-7869
Email Dr. Neil Berinstein
Normal and Malignant B Lymphocytes:
1. Oncogene cooperation with the Bc12 gene in human lymphoid malignancy: Human follicular lymphomas almost universally overexpress the Bc12 proto-oncogene secondary to (14;18) chromosomal translocations. Approximately 50% of these lymphomas will eventually transform to a more malignant invasive lymphoma. The role of other oncogenes or anti-oncogenes in this transformation will be studied. Already we have found mutant P53 genes often occur in conjunction with Bc12 overexpression. The functional significance of these mutations and how they interact in regulating cell proliferation and programmed cell death will be assessed in gene transfer experiments. Other novel oncogenes that cooperate with Bc12 overexpression will be isolated and characterized using Epstein-Barr virus shuttle vectors. These novel genes will be analyzed and their role in normal B cell differentiation will be determined.
2. Active specific immunotherapy of B cell lymphomas: We will develop a murine model to test novel anti-B cell lymphoma vaccine approaches. Using a whole cell vaccination strategy, we will look specifically at the ability of constimulatory molecules such as B7-1, B7-2, and 4-1BB ligand to augment the generation of anti-tumour immunity. Gene transfer technology and pharmacologic agents will be used to generate tumour cell variants that express varied levels of the constimulatory molecule of interest (e.g. B7). The mechanisms responsible for the enhanced immune response will be determined by depleting B and T lymphocyte subsets in in vitro T cell function assays and by using inbred mice deficient in certain lymphocyte subsets. The information obtained from this project will be used to develop similar approaches for the treatment of patients with B cell lymphomas.
3. Secondary l light chain gene rearrangement in mature B lymphocytes: Variation of the immunoglobulin (Ig) idiotype expressed on B cell lymphoma cells is an intrinsic feature occurring during the clonal expansion of many lymphomas that have been studied. In this project we will study the mechanism and control of secondary Ig l light chain rearrangement both at a cellular and molecular level. We will utilize cell line variants already isolated to look for elements and factors that regulate expression of the RAG genes. We will also utilize V region gene probes to map the human Ig l light chain V gene locus. We will attempt to define features that may influence the l light chain V gene repertoire.
List of Key Publications:Link to Pubmed Publications
Stiernholm, N. & Berinstein, N.L. J. 1995. Immunol. 154 , 1748-1761.
Farrugia, M., Kuzniak, B., Berinstein, N. 1994. Alterations of the p53 tumor suppressor gene in diffuse large cell lymphomes with translocations of the c-myc and BCL2 proto-oncogenes. Blood , 83 : 191-198.