Pasqualucci Laura, Klein Ulf
Institute for Cancer Genetics, Department of Pathology & Cell Biology, The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Division of Haematology & Immunology, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds LS9 7TF, UK.
Biomedicines. 2022 Oct 1;10(10):2450. doi: 10.3390/biomedicines10102450.
Most B cell lymphomas arise from the oncogenic transformation of B cells that have undergone the germinal center (GC) reaction of the T cell-dependent immune response, where high-affinity memory B cells and plasma cells are generated. The high proliferation of GC B cells coupled with occasional errors in the DNA-modifying processes of somatic hypermutation and class switch recombination put the cell at a risk to obtain transforming genetic aberrations, which may activate proto-oncogenes or inactivate tumour suppressor genes. Several subtypes of GC lymphomas harbor genetic mutations leading to constitutive, aberrant activation of the nuclear factor-κB (NF-κB) signaling pathway. In normal B cells, NF-κB has crucial biological roles in development and physiology. GC lymphomas highjack these activities to promote tumour-cell growth and survival. It has become increasingly clear that the separate canonical and non-canonical routes of the NF-κB pathway and the five downstream NF-κB transcription factors have distinct functions in the successive stages of GC B-cell development. These findings may have direct implications for understanding how aberrant NF-κB activation promotes the genesis of various GC lymphomas corresponding to the developmentally distinct GC B-cell subsets. The knowledge arising from these studies may be explored for the development of precision medicine approaches aimed at more effective treatments of the corresponding tumours with specific NF-κB inhibitors, thus reducing systemic toxicity. We here provide an overview on the patterns of genetic NF-κB mutations encountered in the various GC lymphomas and discuss the consequences of aberrant NF-κB activation in those malignancies as related to the biology of NF-κB in their putative normal cellular counterparts.
大多数B细胞淋巴瘤起源于经历了T细胞依赖性免疫反应生发中心（GC）反应的B细胞的致癌转化，在该反应中产生了高亲和力记忆B细胞和浆细胞。GC B细胞的高增殖，加上体细胞超突变和类别转换重组的DNA修饰过程中偶尔出现的错误，使细胞有获得转化性基因畸变的风险，这可能激活原癌基因或使肿瘤抑制基因失活。几种GC淋巴瘤亚型存在基因突变，导致核因子-κB（NF-κB）信号通路的组成性、异常激活。在正常B细胞中，NF-κB在发育和生理过程中具有关键的生物学作用。GC淋巴瘤利用这些活性来促进肿瘤细胞的生长和存活。越来越清楚的是，NF-κB途径的独立经典和非经典途径以及五个下游NF-κB转录因子在GC B细胞发育的连续阶段具有不同的功能。这些发现可能对理解异常的NF-κB激活如何促进与发育上不同的GC B细胞亚群相对应的各种GC淋巴瘤的发生具有直接意义。这些研究产生的知识可用于开发精准医学方法，旨在用特定的NF-κB抑制剂更有效地治疗相应肿瘤，从而降低全身毒性。我们在此概述了各种GC淋巴瘤中遇到的NF-κB基因突变更，并讨论了这些恶性肿瘤中异常NF-κB激活的后果，这些后果与假定的正常细胞对应物中NF-κB的生物学特性相关。
