Shen Rhine R, Ferguson David O, Renard Mathilde, Hoyer Katrina K, Kim Unkyu, Hao Xingpei, Alt Frederick W, Roeder Robert G, Morse Herbert C, Teitell Michael A
Department of Pathology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA.
Blood. 2006 Sep 15;108(6):1991-8. doi: 10.1182/blood-2006-02-001354. Epub 2006 May 25.
Most lymphomas arise by transformation of germinal center (GC) B cells. TCL1, a proto-oncogene first recognized for its role in T-cell transformation, also induces GC B-cell malignancies when dysregulated in pEmu-B29-TCL1 transgenic (TCL1-tg) mice. Clonal B-cell lymphomas develop from polyclonal populations with latencies of 4 months or more, suggesting that secondary genetic events are required for full transformation. The goals of this study were to determine the GC-related effects of TCL1 dysregulation that contribute to tumor initiation and to identify companion genetic alterations in tumors that function in disease progression. We report that compared with wild-type (WT) cells, B cells from TCL1-tg mice activated in a manner resembling a T-dependent GC reaction show enhanced resistance to FAS-mediated apoptosis with CD40 stimulation, independent of a B-cell antigen receptor (BCR) rescue signal. Mitogenic stimulation of TCL1-tg B cells also resulted in increased expression of Aicda. These GC-related enhancements in survival and Aicda expression could underlie B-cell transformation. Supporting this notion, no B-cell lymphomas developed for 20 months when TCL1-tg mice were crossed onto an Oct coactivator from B cell (OCA-B)-deficient background to yield mice incapable of forming GCs. Spectral karyotype analyses showed that GC lymphomas from TCL1-tg mice exhibit recurrent chromosome translocations and trisomy 15, with corresponding MYC overexpression. We conclude that pEmu-B29-TCL1 transgenic B cells primed for transformation must experience the GC environment and, for at least some, develop genome instability to become fully malignant.
大多数淋巴瘤起源于生发中心（GC）B细胞的转化。TCL1是一种原癌基因，最初因其在T细胞转化中的作用而被识别，当在pEmu - B29 - TCL1转基因（TCL1 - tg）小鼠中失调时，它也会诱导GC B细胞恶性肿瘤。克隆性B细胞淋巴瘤从多克隆群体发展而来，潜伏期为4个月或更长时间，这表明完全转化需要继发性遗传事件。本研究的目的是确定TCL1失调对肿瘤起始有贡献的GC相关效应，并识别在疾病进展中起作用的肿瘤中的伴随遗传改变。我们报告，与野生型（WT）细胞相比，以类似于T细胞依赖性GC反应的方式激活的TCL1 - tg小鼠的B细胞在CD40刺激下对FAS介导的凋亡表现出增强的抗性，这与B细胞抗原受体（BCR）拯救信号无关。TCL1 - tg B细胞的促有丝分裂刺激也导致Aicda表达增加。这些与GC相关的存活和Aicda表达增强可能是B细胞转化的基础。支持这一观点的是，当TCL1 - tg小鼠与缺乏B细胞Oct共激活因子（OCA - B）的背景杂交以产生无法形成GC的小鼠时，20个月内未发生B细胞淋巴瘤。光谱核型分析表明，TCL1 - tg小鼠的GC淋巴瘤表现出反复的染色体易位和15号染色体三体性，伴有相应的MYC过表达。我们得出结论，准备转化的pEmu - B29 - TCL1转基因B细胞必须经历GC环境，并且至少对一些细胞来说，发展基因组不稳定性才能完全恶变。
