Pediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation program, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberrant epigenetic program controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (MYC). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumor-suppressive activities in several other tumor types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives coordinated suppression of the MYC-driven core circuit supporting neuroblast identity and proliferation, while simultaneously activating an enduring gene program driving mitotic exit and neuronal differentiation. Implications: These findings indicate that targeting phosphorylation of ASCL1 may offer a new approach to development of differentiation therapies in neuroblastoma. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/18/12/1759/F1.large.jpg. Visual Overview

中文翻译：

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原神经转录因子 ASCL1 的去磷酸化重新参与神经母细胞瘤中潜在的有丝分裂后分化程序


儿童癌症通常类似于受困的发育中间状态，无法参与正常的分化程序，典型的例子是由发育中的交感神经系统产生的高风险神经母细胞瘤。神经母细胞瘤细胞类似于被稳定但异常的表观遗传程序捕获的停滞神经母细胞，该程序由发育调节因子核心转录回路的持续表达以及升高的 MYCN 或 MYC (MYC) 控制。转录因子 ASCL1 是神经母细胞瘤的关键主调节因子，并且在其他几种肿瘤类型中具有致癌和肿瘤抑制活性。使用功能突变方法，我们发现防止神经母细胞瘤细胞中 ASCL1 的 CDK 依赖性磷酸化可驱动对支持神经母细胞身份和增殖的 MYC 驱动核心电路的协调抑制，同时激活驱动有丝分裂退出和神经元分化的持久基因程序。意义：这些发现表明，靶向 ASCL1 磷酸化可能为神经母细胞瘤分化疗法的开发提供一种新方法。视觉概述：http://mcr.aacrjournals.org/content/molcanres/18/12/1759/F1.large.jpg。视觉概览