Pleiotropic role for MYCN in medulloblastoma
Pleiotropic role for MYCN in medulloblastoma
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DOI：
10.1101/gad.1907510
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发表时间：
2010-05-15
影响因子：
10.5
通讯作者：
Chesler, Louis
中科院分区：
文献类型：
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作者：
Swartling, Fredrik J.;Grimmer, Matthew R.;Chesler, Louis
髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤。 Sonic Hedgehog (SHH) 信号驱动少数 MB，与促纤维增生病理学和良好的结果相关。然而，大多数与 SHH 无关，表现出经典或大细胞间变性 (LCA) 病理学和不良预后。为了识别常见的信号异常，我们对 mRNA 进行了分析，证明 MYCN 在大多数人类 MB 中错误表达，而在正常小脑中表达可忽略不计。我们通过将 MYCN（和荧光素酶）靶向转基因小鼠的小脑，阐明了其在发病机制中的作用。 MYCN 驱动的 MB 显示出经典或 LCA 病理学，Shh 信号在大约 5% 的肿瘤中被激活，表明 MYCN 可以独立于 Shh 驱动 MB。 MB 以高外显率出现，与 MYCN 在起始中的作用一致。肿瘤负荷与生物发光相关，罕见转移扩散至软脑膜，表明 MYCN 在进展和转移中发挥作用。 MYCN 的短暂药理学下调会导致肿瘤细胞的清除和衰老，并提高生存率。因此，MYCN 的靶向表达有助于 MB 的启动、进展和维持，表明 MYCN 在发病机制中发挥核心作用。
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of MYCN in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting MYCN (and luciferase) to cerebella of transgenic mice. MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in similar to 5% of tumors, demonstrating that MYCN can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for MYCN in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for MYCN in both progression and metastasis. Transient pharmacological down-regulation of MYCN led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of MYCN thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for MYCN in pathogenesis.