Genomic Landscape of Hodgkin Lymphoma.
Genomic Landscape of Hodgkin Lymphoma.
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DOI：
10.3390/cancers13040682
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发表时间：
2021-02-08
期刊：
影响因子：
5.2
通讯作者：
Tzankov A
中科院分区：
文献类型：
--
作者：
Brune MM;Juskevicius D;Haslbauer J;Dirnhofer S;Tzankov A
霍奇金淋巴瘤（HL）由许多反应性的且仅有少数的癌细胞组成，所谓的霍奇金和里德-斯滕伯格（HRS）或淋巴细胞为主（LP）细胞。由于这些细胞的稀缺性，很难在很长一段时间内对其进行高通量的分子研究。在最近开发的方法的帮助下，现在可以分析它们的基因组。本文综述了HRS和LP细胞中发现的影响HL免疫逃避、增殖和规避程序性细胞死亡的遗传改变。了解这些潜在的分子机制是必不可少的，因为它们可能具有预后和预测价值，并有助于改善治疗，特别是对复发性或耐药性疾病的患者。背景资料：霍奇金淋巴瘤（HL）主要由几乎不分布的肿瘤细胞周围的反应性非肿瘤细胞组成，即所谓的霍奇金和里德-斯滕伯格（HRS）或淋巴细胞为主（LP）细胞。这种缺乏阻碍了肿瘤细胞基因组的分析很长一段时间，但最近开发的方法（特别是激光捕获显微切割，流式细胞术/荧光激活细胞分选）促进分子研究，阐明了“霍奇金淋巴瘤”的病理生理学原理。研究方法：我们回顾了过去三十年的相关文献，重点关注经典型和结节型淋巴细胞为主型HL（NLPHL）的基因组图谱，并总结了分子基础。结果如下：首先，由于各种遗传改变，HL的恶性细胞通过改变PDL 1/2、B2 M和MHC I类和II类的表达来逃避免疫系统。其次，由于参与该途径的多个基因的普遍突变，永久激活的JAK/STAT信号传导促进了肿瘤生长。NF-κB化合物和PI 3 K/AKT/mTOR轴的改变阻止了肿瘤细胞的凋亡。此外，EB病毒感染可同时激活JAK/STAT和NF-κB，类似地导致存活率提高和凋亡逃避。最后，表观遗传现象，如启动子甲基化导致B系特异性，肿瘤抑制和免疫调节基因的下调。结论：HL基因组学的蓝图已经奠定，为未来研究其复杂的病理生理学奠定了基础。
Hodgkin lymphoma (HL) is composed of many reactive and only a few cancer cells, so-called Hodgkin and Reed-Sternberg (HRS) or lymphocyte predominant (LP) cells. Due to the scarcity of these cells, it was difficult to perform high-throughput molecular investigations on them for a long time. With the help of recently developed methods, it is now possible to analyze their genomes. This review summarizes the genetic alterations found in HRS and LP cells that impact immune evasion, proliferation and circumvention of programmed cell death in HL. Understanding these underlying molecular mechanisms is essential, as they may be of prognostic and predictive value and help to improve the therapy especially for patients with recurrent or treatment-resistant disease. Background: Hodgkin lymphoma (HL) is predominantly composed of reactive, non-neoplastic cells surrounding scarcely distributed tumor cells, that is, so-called Hodgkin and Reed-Sternberg (HRS) or lymphocyte predominant (LP) cells. This scarcity impeded the analysis of the tumor cell genomes for a long time, but recently developed methods (especially laser capture microdissection, flow cytometry/fluorescence-activated cell sorting) facilitated molecular investigation, elucidating the pathophysiological principles of “Hodgkin lymphomagenesis”. Methods: We reviewed the relevant literature of the last three decades focusing on the genomic landscape of classic and nodular lymphocyte predominant HL (NLPHL) and summarized molecular cornerstones. Results: Firstly, the malignant cells of HL evade the immune system by altered expression of PDL1/2, B2M and MHC class I and II due to various genetic alterations. Secondly, tumor growth is promoted by permanently activated JAK/STAT signaling due to pervasive mutations of multiple genes involved in the pathway. Thirdly, apoptosis of neoplastic cells is prevented by alterations of NF-κB compounds and the PI3K/AKT/mTOR axis. Additionally, Epstein-Barr virus infection can simultaneously activate JAK/STAT and NF-κB, similarly leading to enhanced survival and evasion of apoptosis. Finally, epigenetic phenomena such as promoter hypermethylation lead to the downregulation of B-lineage-specific, tumor-suppressor and immune regulation genes. Conclusion: The blueprint of HL genomics has been laid, paving the way for future investigations into its complex pathophysiology.
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