Bcl-2 and c-Myc co-operate in the Epstein-Barr virus-immortalized human B-cell line GM607 but do not confer tumorigenicity.
Eighty-five percent of follicular lymphomas possess a characteristic t(14;18) translocation that results in the deregulated expression of the proto-oncogene BCL-2. BCL-2 overexpression alone is insufficient for full cellular transformation and at least 1 other genetic event is believed to be necessary for follicular lymphoma development. Deregulated c-Myc expression has previously been shown to cooperate with Bcl-2 to transform murine fibroblast cell lines and lead to tumor development in mice. We have developed a human model system to study early transformation in lymphoid cells using immortalized lymphoblastoid cells. We sequentially introduced BCL-2 and c-MYC, 2 proto-oncogenes known to be involved in the transformation of B cells into Epstein-Barr virus (EBV)-immortalized human B cells. We show that the c-Myc and Bcl-2 overexpression, together with EBV immortalization were insufficient to cause full cellular transformation as measured by cell proliferation rates, soft agar and tumorigenicity assays. These results show that more than 3 genetic hits (EBV infection, Bcl-2 and c-Myc overexpression) were required for the full cellular transformation of human lymphoblastoid cells. However, subtle changes in cellular proliferation and sensitivity to apoptosis were documented, at non-limiting dilutions. These changes may confer a susceptibility to the modified cells such that they are more susceptible to the acquisition of additional genetic changes and evolve towards a fully transformed state. In addition, the model system developed may be suitable for the identification of further known and novel oncogenic events involved in the full transformation of B cells.
Tomlin
Jennifer L
JL
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Guinn
Barbara-Ann
BA
Penn
Linda Z
LZ
Berinstein
Neil L
NL
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015197:Carcinogenicity Tests; D002460:Cell Line; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D015967:Gene Expression Regulation, Viral; D014644:Genetic Variation; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc