Shanmugam Vignesh, Craig Jeffrey W, Hilton Laura K, Nguyen Matthew H, Rushton Christopher K, Fahimdanesh Kian, Lovitch Scott, Ferland Ben, Scott David W, Aster Jon C
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Cancer Program, Broad Institute of MIT and Harvard. Cambridge, MA.
Blood Adv. 2021 Jan 12;5(1):71-83. doi: 10.1182/bloodadvances.2020002995.
Notch receptors participate in a signaling pathway in which ligand-induced proteolysis frees the Notch intracellular domain (NICD), allowing it to translocate to the nucleus, form a transcription complex, and induce target gene expression. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), splenic marginal zone B-cell lymphoma (SMZL), and distinct subsets of diffuse large B-cell lymphoma (DLBCL) are strongly associated with mutations in the 3' end of NOTCH1 or NOTCH2 that disrupt a proline, glutamic acid, serine, and threonine (PEST) degron domain and stabilize NICD1 and NICD2. By contrast, mutations leading to constitutive Notch activation are rare in primary B-cell neoplasms, suggesting that Notch activation is confined to ligand-rich tumor microenvironments, or that cryptic strong gain-of-function mutations have been missed in prior analyses. To test these ideas, we used immunohistochemical stains to screen a broad range of B-cell tumors for Notch activation. Our analyses reveal that among small B-cell neoplasms, NICD2 is primarily detected in SMZL and is a common feature of both NOTCH2 wild-type and NOTCH2-mutated SMZLs, similar to prior findings with NOTCH1 in CLL/SLL. The greatest NOTCH2 activation was observed in NOTCH2-mutated SMZLs, particularly within splenic marginal zones. By contrast, little evidence of NOTCH2 activation was observed in DLBCL, even in NOTCH2-mutated tumors, suggesting that selective pressure for NOTCH2 activation is mainly confined to low-grade B-cell neoplasms, whereas DLBCLs with NOTCH1 mutations frequently showed evidence of ongoing NOTCH1 activation. These observations have important implications for the pathogenic role of Notch and its therapeutic targeting in B-cell lymphomas.
Notch受体参与一种信号通路，其中配体诱导的蛋白水解作用释放出Notch细胞内结构域（NICD），使其能够转运至细胞核，形成转录复合物，并诱导靶基因表达。慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）、脾边缘区B细胞淋巴瘤（SMZL）以及弥漫性大B细胞淋巴瘤（DLBCL）的不同亚组与NOTCH1或NOTCH2 3'端的突变密切相关，这些突变破坏了脯氨酸、谷氨酸、丝氨酸和苏氨酸（PEST）降解结构域，并使NICD1和NICD2稳定。相比之下，导致Notch组成性激活的突变在原发性B细胞肿瘤中很少见，这表明Notch激活局限于富含配体的肿瘤微环境，或者在先前的分析中遗漏了隐匿的强功能获得性突变。为了验证这些观点，我们使用免疫组织化学染色来筛选广泛的B细胞肿瘤中的Notch激活情况。我们的分析表明，在小B细胞肿瘤中，NICD2主要在SMZL中检测到，并且是NOTCH2野生型和NOTCH2突变型SMZL的共同特征，这与先前在CLL/SLL中关于NOTCH1的发现相似。在NOTCH2突变的SMZL中观察到最大程度的NOTCH2激活，特别是在脾边缘区内。相比之下，在DLBCL中几乎没有观察到NOTCH2激活的证据，即使在NOTCH2突变的肿瘤中也是如此，这表明NOTCH2激活的选择性压力主要局限于低级别B细胞肿瘤，而具有NOTCH1突变的DLBCL经常显示出持续的NOTCH1激活的证据。这些观察结果对于Notch在B细胞淋巴瘤中的致病作用及其治疗靶向具有重要意义。
