Zhang Baochun, Wang Zhe, Li Tai, Tsitsikov Erdyni N, Ding Han-Fei
Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA.
Blood. 2007 Jul 15;110(2):743-51. doi: 10.1182/blood-2006-11-058446. Epub 2007 Apr 3.
The NF-kappaB2 gene is recurrently mutated in human lymphoid malignancies. However, a causal relationship between NF-kappaB2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphoid malignancies. We report the generation of transgenic mice with targeted expression of p80HT, a lymphoma-associated NF-kappaB2 mutant, in lymphocytes. The transgenic mice display a marked expansion of peripheral B cell populations and develop predominantly small B cell lymphomas. p80HT expression has no apparent effect on the proliferation of B cells, but renders them specifically resistant to apoptosis induced by cytokine deprivation and mitogenic stimulation. Lymphocytes and lymphoma cells from p80HT mice express high levels of TRAF1, an antiapoptotic protein also implicated in lymphoid malignancies. p80HT binds the TRAF1 promoter in vivo and activates TRAF1 transcription. Moreover, TRAF1 knockdown abrogates the antiapoptotic activity of p80HT and TRAF1 deficiency reestablishes B cell homeostasis in p80HT mice. These findings demonstrate NF-kappaB2 mutation as an oncogenic event in vivo and suggest a molecular pathway for TRAF1 activation in the pathogenesis of lymphomas.
NF-κB2基因在人类淋巴恶性肿瘤中经常发生突变。然而，NF-κB2突变与淋巴瘤发生之间的因果关系尚未确立。该突变如何导致淋巴恶性肿瘤也不清楚。我们报道了在淋巴细胞中靶向表达p80HT（一种与淋巴瘤相关的NF-κB2突变体）的转基因小鼠的产生。转基因小鼠表现出外周B细胞群体的显著扩增，并主要发展为小B细胞淋巴瘤。p80HT表达对B细胞增殖没有明显影响，但使其对细胞因子剥夺和有丝分裂原刺激诱导的凋亡具有特异性抗性。来自p80HT小鼠的淋巴细胞和淋巴瘤细胞表达高水平的TRAF1，一种也与淋巴恶性肿瘤有关的抗凋亡蛋白。p80HT在体内结合TRAF1启动子并激活TRAF1转录。此外，TRAF1敲低消除了p80HT的抗凋亡活性，并且TRAF1缺陷重建了p80HT小鼠中的B细胞稳态。这些发现证明NF-κB2突变是体内的致癌事件，并提示了淋巴瘤发病机制中TRAF1激活的分子途径。
