近日来自纽约大学医学院NYU癌症研究所的研究人员在新研究中发现了弥散性大B细胞淋巴瘤(DLBCL)的一个新的潜在治疗靶点。新研究发现揭示了导致淋巴瘤形成的分子机制，相关研究论文发表在11月23日的《自然》(Nature)杂志上。
文章的资深作者、纽约大学Langone医学中心病理学及肿瘤学教授、霍华德• 休斯医学研究所研究员Michele Pagano博士表示：“我们在B细胞中发现了一个新型的肿瘤抑制因子FBXO11蛋白。新研究结果显示B细胞中FBXO11缺失或突变有可能导致弥散性大B细胞淋巴瘤形成。”
DLBCL是成人淋巴瘤中最常见的一种类型，并且是一组在临床表现、组织形态和预后等多方面具有很大异质性的恶性肿瘤。在欧美国家，DLBCL的发病率约占非霍奇金淋巴瘤(NHL)的31%，在亚洲国家占 NHL大于40%。临床上以迅速增大的无痛性肿块为典型表现，约三分之一患者伴有B症状，骨髓累及的发生率为16%。肿瘤主要发生在淋巴结内，约超过 30%的患者表现为局限的淋巴结外首发病灶。
过去的研究发现大部分的DLBCL患者均显示过量表达B细胞淋巴瘤6蛋白(BCL6)。通过与特异的DNA序列结合，BCL6可调控对B细胞发育和功能起关键作用的基因的转录。当转基因小鼠B细胞中组成性表达BCL6时，小鼠体内形成了与人类相似的DLBCL肿瘤，表明BCL6异常与B细胞淋巴瘤密切相关。尽管此前研究人员曾在某些DLBCL患者中证实BCL6过表达是由于基因异位或启动子突变所致。然而直到现在科学家们对于大部分DLBCLs患者的发病机制仍不是很清楚。
在这项新研究中，纽约大学Langone医学中心的研究人员发现泛素连接酶家族的一个成员SCF(Skp1-Cull-F-box蛋白)复合物的重要组成元件FBXO11在调控BCL6降解中起着关键性的作用。通过B细胞的泛素系统靶向降解BCL6蛋白，细胞内再循环系统帮助限制了不必要的细胞生长，防止细胞恶性转化。FBXO11介导的BCL6降解是防止DLBCL发生的重要机制。
“这些研究发现揭示了B细胞淋巴瘤中过表达BCL6的分子机制，证实了B细胞中FBX011突变和缺失是导致淋巴瘤发病的重要原因。这一研究发现为未来治疗淋巴瘤提供了一个新的有潜力的治疗新策略，”Pagano博士说。
原文摘要：
FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas
BCL6 is the product of a proto-oncogene implicated in the pathogenesis of human B-cell lymphomas1, 2. By binding specific DNA sequences, BCL6 controls the transcription of a variety of genes involved in B-cell development, differentiation and activation. BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adulthood, and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease3, 4. In many DLBCL patients, BCL6 overexpression is achieved through translocation (~40%) or hypermutation of its promoter (~15%). However, many other DLBCLs overexpress BCL6 through an unknown mechanism. Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 (refs 5, 6). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumours in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haplo-insufficient tumour suppressor gene.
