加拿大麦吉尔大学Nada Jabado、Claudia L. Kleinman等研究人员合作发现，组蛋白H3.3 G34突变型中间神经元祖细胞通过PDGFRA导致胶质瘤发生。2020年11月30日，国际知名学术期刊《细胞》在线发表了这一成果。
研究人员表示，高级别神经胶质瘤（HGG）是致命的原发性脑部肿瘤，也是儿童和年轻人死亡的主要原因。这些肿瘤经常在编码组蛋白3（H3）变体或表观遗传修饰因子的基因中具有体细胞突变，并具有明显的神经解剖学和年龄特异性。这些HGG中有30％以上在非经典H3.3变体中带有杂合突变，导致第34位甘氨酸变为精氨酸或缬氨酸（G34R/V）。G34R/V的突变驱动了致命性神经胶质瘤，并显示出精确的区域和时间特异性。但是，目前对G34R/V肿瘤的研究较少，此外，由于它们独特的组织病理学异质性会导致误诊，其比例还可能被低估了。
研究人员发现，50％的G34R/V肿瘤（n=95）带有激活性PDGFRA突变，这些突变在复发时显示出强大的选择压力。尽管被认为是神经胶质瘤，但G34R/V肿瘤实际上出现在表达GSX2/DLX的中间神经元祖细胞中，而G34R/V突变会损害神经元分化。起源谱系可通过将PDGFRA与GSX2调控元件连接的染色质环促进PDGFRA共选择，从而促进PDGFRA过表达和突变。在单细胞水平上，G34R/V肿瘤具有双重神经元/星形胶质特性，并且缺乏少突胶质细胞程序，受到GSX2/DLX介导的细胞命运分化的主动抑制。G34R/V可能对于维持肿瘤至关重要，而突变型PDGFRA具有强致癌性。
总的来说，这些研究结果为致命的肿瘤开辟了新的研究途径。G34R/V胶质瘤是神经元恶性肿瘤，其中神经元祖细胞因G34R/V突变而在分化中停滞，而恶性胶质发生通过共同选择PDGFRA信号来促进肿瘤发生。
附：英文原文
Title: Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis
Author: Carol C.L. Chen, Shriya Deshmukh, Selin Jessa, Djihad Hadjadj, Véronique Lisi, Augusto Faria Andrade, Damien Faury, Wajih Jawhar, Rola Dali, Hiromichi Suzuki, Manav Pathania, Deli A, Frank Dubois, Eleanor Woodward, Steven Hébert, Marie Coutelier, Jason Karamchandani, Steffen Albrecht, Sebastian Brandner, Nicolas De Jay, Tenzin Gayden, Andrea Bajic, Ashot S. Harutyunyan, Dylan M. Marchione, Leonie G. Mikael, Nikoleta Juretic, Michele Zeinieh, Caterina Russo, Nicola Maestro, Angelia V. Bassenden, Peter Hauser, József Virga, Laszlo Bognar, Almos Klekner, Michal Zapotocky, Ales Vicha, Lenka Krskova, Katerina Vanova, Josef Zamecnik, David Sumerauer, Paul G. Ekert, David S. Ziegler, Benjamin Ellezam, Mariella G. Filbin, Mathieu Blanchette, Jordan R. Hansford, Dong-Anh Khuong-Quang, Albert M. Berghuis, Alexander G. Weil, Benjamin A. Garcia, Livia Garzia, Stephen C. Mack, Rameen Beroukhim, Keith L. Ligon, Michael D. Taylor, Pratiti Bandopadhayay, Christoph Kramm
Issue&Volume: 2020-11-30
Abstract: Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomasand show exquisite regional and temporal specificity, suggesting a developmental contextpermissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bearactivating PDGFRA mutations that display strong selection pressure at recurrence. Although consideredgliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation.The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dualneuronal/astroglial identity and lack oligodendroglial programs, actively repressedby GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance,whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadlytumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors arestalled in differentiation by G34R/V mutations and malignant gliogenesis is promotedby co-option of a potentially targetable pathway, PDGFRA signaling.
DOI: 10.1016/j.cell.2020.11.012
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31529-4