The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Blood. 2011 Dec 8;118(24):6380-6. doi: 10.1182/blood-2011-07-367672. Epub 2011 Oct 12.
Impaired apoptosis is a cancer hallmark, and some types of lymphomas and other cancers harbor mutations that directly affect key cell death regulators, such as Bcl-2 family members. However, because the majority of tumors seem to lack such mutations, we are examining the hypothesis that tumorigenesis can be sustained at least initially by the normal expression of specific endogenous pro-survival Bcl-2 family members. We previously demonstrated that the lymphomagenesis in Εμ-myc transgenic mice, which constitutively overexpress the c-Myc oncoprotein in B-lymphoid cells and develop pre-B and B-cell lymphomas, does not require endogenous Bcl-2. In striking contrast, we report here that loss in these mice of its close relative Bcl-x(L) attenuated the pre-neoplastic expansion of pro-B and pre-B cells otherwise driven by c-Myc overexpression, sensitized these cells to apoptosis and ablated lymphoma formation. Remarkably, even loss of a single bcl-x allele delayed the lymphomagenesis. These findings identify Bcl-x(L) as a prerequisite for the emergence of c-Myc-driven pre-B/B lymphoma and suggest that BH3 mimetic drugs may provide a prophylactic strategy for c-Myc-driven tumors.
细胞凋亡受损是癌症的一个标志，一些类型的淋巴瘤和其他癌症具有直接影响关键细胞死亡调节剂的突变，如 Bcl-2 家族成员。然而，由于大多数肿瘤似乎缺乏这种突变，我们正在检验这样一种假说，即肿瘤发生至少最初可以通过特定内源性生存促进 Bcl-2 家族成员的正常表达来维持。我们之前证明，在 Εμ-myc 转基因小鼠中，c-Myc 癌蛋白在 B 淋巴细胞中持续过表达并发展出前 B 和 B 细胞淋巴瘤，这种淋巴瘤的发生并不需要内源性 Bcl-2。与此形成鲜明对比的是，我们在这里报告说，在这些小鼠中，其近亲 Bcl-x(L) 的缺失减弱了由 c-Myc 过表达驱动的前 B 和前 B 细胞的肿瘤前扩张，使这些细胞对细胞凋亡敏感并消除了淋巴瘤的形成。值得注意的是，即使缺失单个 bcl-x 等位基因也会延迟淋巴瘤的发生。这些发现将 Bcl-x(L) 确定为 c-Myc 驱动的前 B/B 淋巴瘤出现的必要条件，并表明 BH3 模拟药物可能为 c-Myc 驱动的肿瘤提供一种预防策略。
