Development and epigenetic regulation of Atypical teratoid/rhabdoid tumors in the context of cell-of-origin and halted cell differentiation.

IF 3.7 Q1 CLINICAL NEUROLOGY Neuro-oncology advances Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI:10.1093/noajnl/vdae162
Laura Huhtala, Goktug Karabiyik, Kirsi J Rautajoki
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Abstract

Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants. The only characteristic, recurrent genetic aberration of AT/RTs is biallelic inactivation of SMARCB1 (or SMARCA4). These genes are members of the mSWI/SNF chromatin-remodeling complex, which regulates various developmental processes, including neural differentiation. This review explores AT/RT subgroups regarding their distinct SMARCB1 loss-of-function mechanisms, molecular features, and patient characteristics. Additionally, it addresses the ongoing debate about the oncogenic relevance of cell-of-origin, examining the influence of developmental stage and lineage commitment of the seeding cell on tumor malignancy and other characteristics. Epigenetic dysregulation, particularly through the regulation of histone modifications and DNA hypermethylation, has been shown to play an integral role in AT/RTs' malignancy and differentiation blockage, maintaining cells in a poorly differentiated state via the insufficient activation of differentiation-related genes. Here, the differentiation blockage and its contribution to malignancy are also explored in a cellular context. Understanding these mechanisms and AT/RT heterogeneity is crucial for therapeutic improvements against AT/RTs.

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非典型畸胎瘤/横纹肌瘤在原发细胞和停止细胞分化背景下的发展和表观遗传调控。
非典型畸形/横纹肌瘤(AT/RTs)是一种侵袭性脑肿瘤,主要见于婴儿。AT/RTs的唯一特征性、复发性遗传畸变是SMARCB1(或SMARCA4)的双偶联失活。这些基因是 mSWI/SNF 染色质重塑复合体的成员,该复合体调控包括神经分化在内的各种发育过程。本综述探讨了AT/RT亚组不同的SMARCB1功能缺失机制、分子特征和患者特征。此外,本综述还探讨了目前关于原发细胞致癌相关性的争论,研究了播种细胞的发育阶段和品系承诺对肿瘤恶性程度和其他特征的影响。表观遗传失调,特别是通过组蛋白修饰和DNA高甲基化的调控,已被证明在AT/RTs的恶性和分化阻滞中发挥了不可或缺的作用,通过分化相关基因的激活不足,使细胞维持在低分化状态。本文还从细胞角度探讨了分化受阻及其对恶性肿瘤的影响。了解这些机制和AT/RT的异质性对于改善针对AT/RT的治疗至关重要。
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CiteScore
6.20
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审稿时长
12 weeks
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