美国纪念斯隆凯特琳癌症中心Richard M. White和LORENZ STUDER课题组合作取得最新进展。他们发现发育染色质程序决定黑色素瘤的致癌能力。相关论文于2021年9月3日发表在《科学》杂志上。

使用人类多能干细胞来源的癌症模型与斑马鱼转基因的组合，他们证明 BRAFV600E 的转化能力以及其他突变取决于原始细胞中存在的内在转录程序。在这两种系统中，黑色素细胞对突变的反应较弱，而神经嵴和成黑色素细胞群都容易转化。分析表明，祖细胞具有更高的染色质修饰酶表达，例如 ATAD2，这是一种黑色素瘤能力因子，可与 SOX10 形成复合物，并允许下游致癌和神经嵴程序的表达。这些数据表明致癌能力是由发育染色质因子的调节介导的，然后允许对这些致癌基因做出适当的反应。

据悉，致癌基因仅在某些细胞环境下转化细胞，这种现象称为致癌能力。

附：英文原文

Title: Developmental chromatin programs determine oncogenic competence in melanoma

Author: Arianna Baggiolini, Scott J. Callahan, Emily Montal, Joshua M. Weiss, Tuan Trieu, Mohita M. Tagore, Sam E. Tischfield, Ryan M. Walsh, Shruthy Suresh, Yujie Fan, Nathaniel R. Campbell, Sarah C. Perlee, Nathalie Saurat, Miranda V. Hunter, Theresa Simon-Vermot, Ting-Hsiang Huang, Yilun Ma, Travis Hollmann, Satish K. Tickoo, Barry S. Taylor, Ekta Khurana, Richard P. Koche, Lorenz Studer, Richard M. White

Issue&Volume: 2021-09-03

Abstract: Oncogenes only transform cells under certain cellular contexts, a phenomenon called oncogenic competence. Using a combination of a human pluripotent stem cell–derived cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAFV600E along with additional mutations depends on the intrinsic transcriptional program present in the cell of origin. In both systems, melanocytes are less responsive to mutations, whereas both neural crest and melanoblast populations are readily transformed. Profiling reveals that progenitors have higher expression of chromatin-modifying enzymes such as ATAD2, a melanoma competence factor that forms a complex with SOX10 and allows for expression of downstream oncogenic and neural crest programs. These data suggest that oncogenic competence is mediated by regulation of developmental chromatin factors, which then allow for proper response to those oncogenes.

DOI: abc1048

Source: https://www.science.org/doi/10.1126/science.abc1048