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NOTCH信号通路及其在成熟B细胞恶性肿瘤中的突变

The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies.

作者信息

Arruga Francesca, Vaisitti Tiziana, Deaglio Silvia

机构信息

Italian Institute for Genomic Medicine, Turin, Italy.

Department of Medical Sciences, University of Torino, Turin, Italy.

出版信息

Front Oncol. 2018 Nov 26;8:550. doi: 10.3389/fonc.2018.00550. eCollection 2018.

DOI:10.3389/fonc.2018.00550
PMID:30534535
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6275466/
Abstract

The systematic application of next-generation sequencing to large cohorts of oncologic samples has opened a Pandora's box full of known and novel genetic lesions implicated in different steps of cancer development and progression. Narrowing down to B cell malignancies, many previously unrecognized genes emerged as recurrently mutated. The challenge now is to determine how the mutation in a given gene affects the biology of the disease, paving the way to functional genomics studies. Mutations in NOTCH family members are shared by several disorders of the B series, even if with variable frequencies and mutational patterns. predictions, revealed that mutations occurring in NOTCH receptors, despite being qualitatively different, may have similar effects on protein processing, ultimately leading to enhanced pathway activation. The discovery of mutations occurring also in downstream players, either potentiating positive signals or compromising negative regulators, indicates that multiple mechanisms in neoplastic B cells concur to activate NOTCH pathway. These findings are supported by results obtained in chronic lymphocytic leukemia and splenic marginal zone B cell lymphoma where deregulation of NOTCH signaling has been functionally characterized. The emerging picture confirms that NOTCH signaling is finely tuned in cell- and microenvironment-dependent ways. In B cell malignancies, it contributes to the regulation of proliferation, survival and migration. However, deeper biological studies are needed to pinpoint the contribution of NOTCH in the hierarchy of events driving B cells transformation, keeping in mind its role in normal B cells development. Because of its relevance in leukemia and lymphoma biology, the NOTCH pathway might represent an appealing therapeutic target: the next few years will tell whether this potential will be fulfilled.

摘要

将下一代测序系统应用于大量肿瘤样本队列,打开了一个潘多拉魔盒,其中充满了与癌症发生和发展不同阶段相关的已知和新型基因损伤。具体到B细胞恶性肿瘤,许多以前未被识别的基因出现反复突变。现在的挑战是确定特定基因中的突变如何影响疾病生物学,为功能基因组学研究铺平道路。NOTCH家族成员中的突变在几种B系疾病中都有出现,尽管频率和突变模式各不相同。预测结果显示,NOTCH受体中发生的突变尽管在性质上有所不同,但可能对蛋白质加工有相似的影响,最终导致通路激活增强。在下游分子中也发现了突变,这些突变要么增强正信号,要么损害负调节因子,这表明肿瘤性B细胞中的多种机制共同激活NOTCH通路。慢性淋巴细胞白血病和脾边缘区B细胞淋巴瘤的研究结果支持了这些发现,在这些疾病中,NOTCH信号通路的失调已在功能上得到了表征。新出现的情况证实,NOTCH信号通路是以细胞和微环境依赖的方式进行精细调节的。在B细胞恶性肿瘤中,它有助于调节增殖、存活和迁移。然而,需要更深入的生物学研究来确定NOTCH在驱动B细胞转化的事件层级中的作用,同时牢记其在正常B细胞发育中的作用。由于其在白血病和淋巴瘤生物学中的相关性,NOTCH通路可能是一个有吸引力的治疗靶点:未来几年将揭示这一潜力是否能够实现。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf7/6275466/e58459e40dac/fonc-08-00550-g0005.jpg
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