美国斯隆·凯特琳纪念癌症中心Viviane Tabar研究组取得最新进展。他们在H3.3G34R突变型神经胶质瘤hESC模型中剖析区域身份效应和人类特异性NOTCH2NL的致癌作用。相关论文发表在2021年2月24日的《细胞-干细胞》杂志上。

他们开发了基于人类胚胎干细胞（hESC）的H3.3G34R突变型神经胶质瘤模型，该模型概括了肿瘤的关键特征，具有对前脑神经元祖细胞而不是后脑前体神经元的细胞类型特异性。他们显示H3.3G34R、ATRX和TP53突变协同影响可变RNA剪接事件，特别是内含子保守抑制。这导致Notch途径的组分特别是人类特异性基因家族NOTCH2NL的表达增加。

他们还发现了通过在某些H3.3G34R突变肿瘤中的基因座进行基因组扩增来增强NOTCH2NL表达的平行机制。 这些发现证明了一种新的机制，通过该机制可以选择导致人类大脑更大的进化途径来驱动肿瘤生长。

据悉，H3.3G34R突变型神经胶质瘤是脑半球的致死性肿瘤，其区域特异性和致瘤性机制尚不清楚。

附：英文原文

Title: Dissecting the impact of regional identity and the oncogenic role of human-specific NOTCH2NL in an hESC model of H3.3G34R-mutant glioma

Author: Kosuke Funato, Ryan C. Smith, Yuhki Saito, Viviane Tabar

Issue&Volume: 2021-02-24

Abstract: H3.3G34R-mutant gliomas are lethal tumors of the cerebral hemispheres with unknownmechanisms of regional specificity and tumorigenicity. We developed a human embryonicstem cell (hESC)-based model of H3.3G34R-mutant glioma that recapitulates the keyfeatures of the tumors with cell-type specificity to forebrain interneuronal progenitorsbut not hindbrain precursors. We show that H3.3G34R, ATRX, and TP53 mutations cooperatively impact alternative RNA splicing events, particularly suppressionof intron retention. This leads to increased expression of components of the Notchpathway, notably NOTCH2NL, a human-specific gene family. We also uncover a parallel mechanism of enhanced NOTCH2NL expression via genomic amplification of its locus in some H3.3G34R-mutant tumors.These findings demonstrate a novel mechanism whereby evolutionary pathways that leadto larger brain size in humans are co-opted to drive tumor growth.

DOI: 10.1016/j.stem.2021.02.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00053-9