Leung Carly, Lingbeek Merel, Shakhova Olga, Liu James, Tanger Ellen, Saremaslani Parvin, Van Lohuizen Maarten, Marino Silvia
Institute of Clinical Pathology, Department of Pathology, University of Zürich, Schmelzbergstrasse 12, 8091 Zürich, Switzerland.
Nature. 2004 Mar 18;428(6980):337-41. doi: 10.1038/nature02385.
Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated. Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to medulloblastoma development. We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, these findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for Bmi1-containing polycomb complexes in proliferation of cerebellar precursor cells.
多梳家族基因Bmi1的过表达通过抑制细胞周期蛋白依赖性激酶抑制因子2a（Cdkn2a，也称为Ink4a/Arf）促进细胞增殖并诱发白血病。相反，Bmi1的缺失会导致血液学缺陷和严重的进行性神经异常，其中Ink4a/Arf基因座的去抑制起着关键作用。在此，我们表明Bmi1在小鼠和人类的增殖性小脑前体细胞中强烈表达。利用Bmi1基因敲除小鼠，我们证明了Bmi1在颗粒细胞前体的体内和体外克隆扩增中起关键作用。这些祖细胞的增殖失调，通过音猬因子（Shh）信号通路的激活，导致髓母细胞瘤的发生。我们还证明，在相当一部分原发性人类髓母细胞瘤中，BMI1和patched（PTCH）存在相关的过表达，提示SHH信号通路被激活。连同在小脑颗粒细胞培养物中添加Shh或过表达Shh靶标Gli1后Bmi1表达的快速诱导，这些发现表明BMI1过表达是髓母细胞瘤发病机制中的一种替代或附加机制，并突出了含Bmi1的多梳复合物在小脑前体细胞增殖中的作用。
