Delbridge A R D, Grabow S, Bouillet P, Adams J M, Strasser A
1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
Oncogene. 2015 Apr 2;34(14):1872-6. doi: 10.1038/onc.2014.132. Epub 2014 May 26.
Genomic analyses revealed that many cancers have acquired abnormalities in their expression of pro- or anti-apoptotic members of the BCL-2 protein family. It is, however, unknown whether changes in pro- or anti-apoptotic BCL-2 family members have similar impact on tumorigenesis or whether changes in one subgroup have disproportionate impact. We compared the consequences of concomitant loss of anti-apoptotic Bclx and pro-apoptotic Bim on MYC-induced lymphomagenesis. Whereas only loss of both Bclx alleles markedly forestalled tumorigenesis, loss of a single Bim allele overcame this blockade. Conversely, loss of even a single Bim allele sufficed to substantially accelerate lymphomagenesis, and only loss of both but not loss of a single allele of Bclx could attenuate this acceleration. The evidence that modest (two-fold) monoallelic changes in the expression of at least some BH3-only proteins can profoundly impact tumorigenesis suggests that such aberrations, imposed by epigenetic or genetic changes, may expedite tumorigenesis more effectively than elevated expression of pro-survival BCL-2 family members. These findings further our understanding of the mechanisms of lymphomagenesis and possibly also cancer therapy.
基因组分析显示，许多癌症在其BCL-2蛋白家族促凋亡或抗凋亡成员的表达上出现了异常。然而，促凋亡或抗凋亡的BCL-2家族成员的变化对肿瘤发生是否有相似的影响，或者一个亚组的变化是否有不成比例的影响，目前尚不清楚。我们比较了抗凋亡蛋白Bclx和促凋亡蛋白Bim同时缺失对MYC诱导的淋巴瘤发生的影响。只有两个Bclx等位基因都缺失才会显著延缓肿瘤发生，而单个Bim等位基因的缺失则克服了这种阻滞。相反，即使单个Bim等位基因的缺失也足以显著加速淋巴瘤的发生，只有两个Bclx等位基因都缺失而不是单个等位基因缺失才能减弱这种加速作用。至少一些仅含BH3结构域的蛋白表达发生适度（两倍）单等位基因变化就能深刻影响肿瘤发生，这一证据表明，由表观遗传或基因变化导致的此类畸变可能比促生存BCL-2家族成员的高表达更有效地加速肿瘤发生。这些发现加深了我们对淋巴瘤发生机制的理解，也可能有助于癌症治疗。
