Tomlin Jennifer L, Guinn Barbara-Ann, Penn Linda Z, Berinstein Neil L
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Leuk Lymphoma. 2005 Apr;46(4):581-92. doi: 10.1080/10428190400019867.
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.
85%的滤泡性淋巴瘤具有特征性的t(14;18)易位，这导致原癌基因BCL-2的表达失调。仅BCL-2的过表达不足以实现完全的细胞转化，并且至少另一个基因事件被认为是滤泡性淋巴瘤发展所必需的。先前已表明，失调的c-Myc表达与Bcl-2协同作用可转化小鼠成纤维细胞系并导致小鼠肿瘤发生。我们开发了一种人类模型系统，使用永生化的淋巴母细胞系来研究淋巴细胞的早期转化。我们将BCL-2和c-MYC这两个已知参与B细胞转化的原癌基因依次导入爱泼斯坦-巴尔病毒（EBV）永生化的人类B细胞中。我们发现，通过细胞增殖率、软琼脂和致瘤性试验测量，c-Myc和Bcl-2的过表达以及EBV永生化不足以引起完全的细胞转化。这些结果表明，人类淋巴母细胞系的完全细胞转化需要超过3次基因打击（EBV感染、Bcl-2和c-Myc过表达）。然而，在非极限稀释条件下，记录到了细胞增殖和对凋亡敏感性的细微变化。这些变化可能使修饰后的细胞具有易感性，使其更容易获得额外的基因变化并朝着完全转化的状态发展。此外，所开发的模型系统可能适用于鉴定参与B细胞完全转化的更多已知和新的致癌事件。
