PDF(Pubmed)
Abstract：
Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ~30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe the first zebrafish model of SHH MB using CRISPR to mutate ptch1, the primary genetic driver in human SHH MB. These tumors rapidly arise adjacent to the valvula cerebelli and resemble human SHH MB by histology and comparative genomics. In addition, ptch1-deficient MB tumors with loss of tp53 have aggressive tumor histology and significantly worse survival outcomes, comparable to human patients. The simplicity and scalability of the ptch1 MB model makes it highly amenable to CRISPR-based genome editing screens to identify genes required for SHH MB tumor formation in vivo, and here we identify the grk3 kinase as one such target.
摘要：
髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤，分为三个主要亚组。Sonichedgehog（SHH）亚组占所有MB病例的30％，并且根据TP53状态具有显着的生存差异。这里,我们描述了使用CRISPR突变ptch1的SHHMB的第一个斑马鱼模型，人类SHHMB的主要遗传驱动因素。这些肿瘤在小脑瓣膜附近迅速出现，并通过组织学和比较基因组学类似于人类SHHMB。此外,ptch1缺陷型MB肿瘤与tp53缺失具有侵袭性肿瘤组织学和显著较差的生存结果，与人类患者相当。ptch1MB模型的简单性和可扩展性使其高度适合于基于CRISPR的基因组编辑屏幕，以识别体内SHHMB肿瘤形成所需的基因。在这里，我们将grk3激酶确定为一个这样的靶标。
