Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Center, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Mol Cancer Res. 2020 Dec;18(12):1759-1766. doi: 10.1158/1541-7786.MCR-20-0693. Epub 2020 Oct 12.
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 (). 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.
儿科癌症通常类似于被困的发育中间状态，无法参与正常的分化程序，以高危神经母细胞瘤为代表，它起源于发育中的交感神经系统。神经母细胞瘤细胞类似于被稳定但异常的表观遗传程序困住的未成熟神经细胞，该程序受发育调节剂核心转录电路的持续表达以及 MYCN 或 MYC 的升高控制（）。转录因子 ASCL1 是神经母细胞瘤的关键主调控因子，在其他几种肿瘤类型中具有致癌和肿瘤抑制活性。通过功能突变方法，我们发现阻止神经母细胞瘤细胞中 CDK 依赖性 ASCL1 磷酸化可协同抑制支持神经母细胞特性和增殖的 MYC 驱动核心电路，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，针对 ASCL1 的磷酸化可能为神经母细胞瘤分化治疗的发展提供新方法。直观描述：http://mcr.aacrjournals.org/content/molcanres/18/12/1759/F1.large.jpg。
