Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.
School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
Nat Commun. 2024 Jul 11;15(1):5585. doi: 10.1038/s41467-024-49871-0.
MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.
MYCN 癌基因扩增在侵袭性儿童神经母细胞瘤中经常观察到。使用神经母细胞瘤易感转基因小鼠中的无偏大规模诱变筛选，我们在转录共抑制因子 Runx1t1 中鉴定出一个单一的种系点突变，该突变消除了 MYCN 驱动的肿瘤发生。该功能丧失突变破坏了 Runx1t1 内高度保守的锌指结构域。在独立的 Runx1t1 敲除小鼠模型中，删除一个 Runx1t1 等位基因也足以防止 MYCN 驱动的神经母细胞瘤发生，并逆转神经节增生，这是肿瘤发生的已知先决条件。在人神经母细胞瘤细胞中沉默 RUNX1T1 可减少体外集落形成，并抑制体内肿瘤生长。此外，RUNX1T1 敲低抑制 PAX3-FOXO1 融合驱动的横纹肌肉瘤和 MYC 驱动的小细胞肺癌细胞的活力。尽管 Runx1t1 在 MYCN 驱动的肿瘤发生中起作用，但这两个基因都不会直接调节另一个基因。我们表明 RUNX1T1 是 HAND2 募集的转录 LSD1-CoREST3-HDAC 抑制复合物的一部分，该复合物募集到增强子区域以调节染色质可及性和细胞命运途径基因。
