脾边缘区淋巴瘤的基因组和分子图谱、生物学和临床意义

Amatta Mirandari, H. Parker, M. Ashton-Key, Ben Stevens, R. Walewska, K. Stamatopoulos, Dean Bryant, D. Oscier, Jane Gibson, J. Strefford
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摘要

脾边缘区淋巴瘤(SMZL)是一种罕见的B细胞淋巴瘤,主要是非淋巴性淋巴瘤,占淋巴肿瘤的2%以下。然而,尽管目前已有治疗方法,但仍有约30%的患者生存期较短,尤其是5%-15%转化为大细胞淋巴瘤的病例,预后更差。越来越多的证据表明,SMZL的分子发病机制主要由微环境诱因和细胞内在畸变决定。免疫遗传学研究揭示了免疫球蛋白基因库中的偏差,表明抗原选择的作用。此外,细胞遗传学研究还发现了反复出现的染色体异常,如第7号染色体长臂缺失,但具体的疾病相关基因仍难以确定。我们根据有限的病例对SMZL基因突变情况的了解发现,KLF2、NOTCH2和TP53以及重要的B细胞分化通路中的基因会反复发生突变。这些突变可聚集在具有不同染色体病变模式、免疫遗传学特征、转录特征、免疫微环境和临床结果的患者亚群中。关于SMZL的表观遗传学,最初的DNA甲基化分析揭示了表观遗传学上不同的患者亚群,其中一个亚群的特点是多聚核酸抑制复合体2(PRC2)成分的表达升高。此外,研究还表明,根据甲基化数据推断,有大量历史性细胞分裂证据的患者无治疗生存率较低。本综述概述了我们目前对 SMZL 分子基础的理解及其对患者预后的影响。此外,它还探讨了现有的知识差距,提出了未来的研究方向,并讨论了对该疾病的全面分子认识将如何改善患者的管理和治疗选择。
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The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications
Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5–15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL’s mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL’s molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients.
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