B 细胞淋巴瘤 6 (BCL6)：从体液免疫的主调节因子到儿科癌症的致癌驱动因素,Molecular Cancer Research

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B 细胞淋巴瘤 6 (BCL6)：从体液免疫的主调节因子到儿科癌症的致癌驱动因素
Molecular Cancer Research ( IF 4.1 ) Pub Date : 2022-09-27 , DOI: 10.1158/1541-7786.mcr-22-0567
Tabitha McLachlan _{1,

2} , William C Matthews _{1,

2} , Evangeline R Jackson _{1,

2} , Dilana E Staudt _{1,

2} , Alicia M Douglas _{1,

2} , Izac J Findlay _{1,

2} , Mika L Persson _{1,

2} , Ryan J Duchatel _{1,

2} , Abdul Mannan _{1,

2} , Zacary P Germon _{1,

2} , Matthew D Dun _{1,

2}

Affiliation

B 细胞淋巴瘤 6 (BCL6) 是成人和儿童癌症中的一种原癌基因，首先在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中发现，它作为肿瘤抑制因子 TP53 的抑制因子，赋予淋巴瘤生存、保护和维持细胞。正常 B 细胞中的 BCL6 表达对于通过生发中心 (GC) 的启动和维持来调节体液免疫至关重要。据信，它在 B 细胞产生高亲和力免疫球蛋白（识别并结合特定抗原）过程中的作用巩固了其作为癌基因的功能。已知 BCL6 可以驱动白血病起始细胞 (LIC) 的自我更新能力，在急性淋巴细胞白血病 (ALL)、急性髓性白血病 (AML) 和胶质母细胞瘤 (GBM) 中 BCL6 高表达，与疾病进展和治疗耐药相关。BCL6 驱动的治疗耐药性的机制尚未被揭示；然而，在临床环境中，高活性被认为会带来不良预后。BCL6 的关键结合伙伴 BCL6 辅阻遏物 (BCOR) 在儿科癌症中经常发生突变，并且似乎与 BCL6 协同作用。在此，我们使用公开数据表明，BCL6 在儿童脑肿瘤中普遍过度表达，与 BCOR 成反比，这凸显了在这些通常致命且无法治疗的癌症中靶向 BCL6 的潜力。在这篇综述中，我们总结了 BCL6 在儿科癌症中的已知信息（作用、效果、机制），重点介绍了 BCL6 功能、体液免疫和肿瘤发生的两个方面，并回顾了 BCL6 抑制剂并强调了有待改进的领域小儿癌症患者的结果。

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B-cell Lymphoma 6 (BCL6): From Master Regulator of Humoral Immunity to Oncogenic Driver in Pediatric Cancers

B-cell lymphoma 6 (BCL6) is a protooncogene in adult and pediatric cancers, first identified in diffuse large B-cell lymphoma (DLBCL) where it acts as a repressor of the tumor suppressor TP53, conferring survival, protection, and maintenance of lymphoma cells. BCL6 expression in normal B cells is fundamental in the regulation of humoral immunity, via initiation and maintenance of the germinal centers (GC). Its role in B cells during the production of high affinity immunoglobins (that recognize and bind specific antigens) is believed to underpin its function as an oncogene. BCL6 is known to drive the self-renewal capacity of leukemia-initiating cells (LIC), with high BCL6 expression in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and glioblastoma (GBM) associated with disease progression and treatment resistance. The mechanisms underpinning BCL6-driven therapy resistance are yet to be uncovered; however, high activity is considered to confer poor prognosis in the clinical setting. BCL6’s key binding partner, BCL6 corepressor (BCOR), is frequently mutated in pediatric cancers and appears to act in concert with BCL6. Using publicly available data, here we show that BCL6 is ubiquitously overexpressed in pediatric brain tumors, inversely to BCOR, highlighting the potential for targeting BCL6 in these often lethal and untreatable cancers. In this review, we summarize what is known of BCL6 (role, effect, mechanisms) in pediatric cancers, highlighting the two sides of BCL6 function, humoral immunity, and tumorigenesis, as well as to review BCL6 inhibitors and highlight areas of opportunity to improve the outcomes of patients with pediatric cancer.

更新日期：2022-09-27

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