Michael Lowell Evan, Westerman Bart A, Ermilov Alexandre N, Wang Aiqin, Ferris Jennifer, Liu Jianhong, Blom Marleen, Ellison David W, van Lohuizen Maarten, Dlugosz Andrzej A
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109-0932, USA.
Neoplasia. 2008 Dec;10(12):1343-9, 5p following 1349. doi: 10.1593/neo.81078.
Inappropriate Hedgehog (Hh) signaling underlies development of a subset of medulloblastomas, and tumors with elevated HH signaling activity express the stem cell self-renewal gene BMI1. To test whether Bmi1 is required for Hh-driven medulloblastoma development, we varied Bmi1 gene dosage in transgenic mice expressing an oncogenic Hh effector, SmoA1, driven by a glial fibrillary acidic protein (GFAP) promoter. Whereas 100% of SmoA1; Bmi1(+/+) or SmoA1;Bmi1(+/-) mice examined between postnatal (P) days 14 and 26 had typical medulloblastomas (N = 29), tumors were not detected in any of the SmoA1;Bmi1(-/-) animals examined (N = 6). Instead, small ectopic collections of cells were present in the region of greatest tumor load in SmoA1 animals, suggesting that medulloblastomas were initiated but failed to undergo expansion into frank tumors. Cells within these Bmi1(-/-) lesions expressed SmoA1 but were largely nonproliferative, in contrast to cells in Bmi1(+/+) tumors (6.2% vs 81.9% PCNA-positive, respectively). Ectopic cells were negative for the progenitor marker nestin, strongly GFAP-positive, and highly apoptotic, relative to Bmi1(+/+) tumor cells (29.6% vs 6.3% TUNEL-positive). The alterations in proliferation and apoptosis in SmoA1;Bmi1(-/-) ectopic cells are associated with reduced levels of Cyclin D1 and elevated expression of cyclin-dependent kinase inhibitor p19(Arf), two inversely regulated downstream targets of Bmi1. These data provide the first demonstration that Bmi1 is required for spontaneous de novo development of a solid tumor arising in the brain, suggest a crucial role for Bmi1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion, and implicate Bmi1 as a key factor required for Hh pathway-driven tumorigenesis.
异常的刺猬信号通路（Hh）是一部分髓母细胞瘤发生发展的基础，且Hh信号活性升高的肿瘤表达干细胞自我更新基因BMI1。为了检测Bmi1是否是Hh驱动的髓母细胞瘤发生发展所必需的，我们在由胶质纤维酸性蛋白（GFAP）启动子驱动的、表达致癌性Hh效应蛋白SmoA1的转基因小鼠中改变Bmi1基因剂量。在出生后（P）14至26天检查的SmoA1;Bmi1(+/+)或SmoA1;Bmi1(+/-)小鼠中，100%患有典型的髓母细胞瘤（N = 29），而在检查的任何SmoA1;Bmi1(-/-)动物中均未检测到肿瘤（N = 6）。相反，在SmoA1动物肿瘤负荷最大的区域存在小的异位细胞聚集，这表明髓母细胞瘤已起始，但未能发展为明显的肿瘤。与Bmi1(+/+)肿瘤中的细胞相比，这些Bmi1(-/-)病变中的细胞表达SmoA1，但大多不增殖（分别为6.2%和81.9%的增殖细胞核抗原（PCNA）阳性）。相对于Bmi1(+/+)肿瘤细胞，异位细胞的祖细胞标志物巢蛋白呈阴性，胶质纤维酸性蛋白呈强阳性且高度凋亡（分别为29.6%和6.3%的末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）阳性）。SmoA1;Bmi1(-/-)异位细胞增殖和凋亡的改变与细胞周期蛋白D1水平降低和细胞周期蛋白依赖性激酶抑制剂p19(Arf)表达升高有关，这是Bmi1的两个反向调节的下游靶点。这些数据首次证明Bmi1是脑内实体瘤自发从头发生所必需的，提示依赖Bmi1、表达巢蛋白的祖细胞在髓母细胞瘤扩展中起关键作用，并表明Bmi1是Hh通路驱动的肿瘤发生所必需的关键因子。
