LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
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DOI：
10.1182/blood.2019002654
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发表时间：
2020-08-06
期刊：
影响因子：
20.3
通讯作者：
Takaori-Kondo, Akifumi
中科院分区：
文献类型：
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作者：
Jo, Tomoyasu;Nishikori, Momoko;Takaori-Kondo, Akifumi
线性泛素链组装复合物（LUBAC）是NF-κ B信号传导的关键调节因子。HOIP（LUBAC的催化亚基）的活化单核苷酸多态性在活化B细胞样（ABC）弥漫性大B细胞淋巴瘤（DLBCL）患者中富集，并且与LUBAC活性平行的HOIP表达在ABC-DLBCL样本中升高。因此，为了阐明LUBAC在淋巴瘤发生中的确切作用，我们建立了B细胞中HOIP表达增强的小鼠模型。有趣的是，HOIP表达增强促进了MYD 88激活突变驱动的DLBCL样B细胞淋巴瘤发生。发展的淋巴瘤细胞部分地与人类DLBCL共享体细胞基因突变，具有典型AID突变模式的频率增加。体外分析显示HOIP过表达通过NF-κ B活化保护B细胞免于DNA损伤诱导的细胞死亡，并且对人DLBCL数据库的分析显示HOIP的表达与代表细胞凋亡信号传导调节的基因特征以及NF-κ B信号传导正相关。这些结果表明HOIP通过防止细胞死亡和增强NF-κ B信号传导促进淋巴瘤发生，导致AIDS介导的突变的积累。此外，一种特异性抑制LUBAC的天然化合物在小鼠移植模型中显示出抑制肿瘤生长。总的来说，我们的数据表明，LUBAC是至关重要的参与B细胞淋巴瘤的发生，通过保护对DNA损伤诱导的细胞死亡，是一个合适的治疗目标的B细胞淋巴瘤。
The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-kappa B signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-kappa B activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-kappa B signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-kappa B signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage-induced cell death and is a suitable therapeutic target for B-cell lymphomas.