Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Blood. 2012 Aug 23;120(8):1668-77. doi: 10.1182/blood-2012-02-406074. Epub 2012 Jul 12.
Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, remains a partially curable disease. Genetic alterations affecting components of NF-κB signaling pathways occur frequently in DLBCL. Almost all activated B cell-like (ABC) DLBCL, which is the least curable group among the 3 major subtypes of this malignancy, and a substantial fraction of germinal center B cell-like (GCB) DLBCL exhibit constitutive NF-κB pathway activity. It has been demonstrated that ABC-DLBCL cells require such activity for proliferation and survival. Therefore, inhibition of NF-κB activation in DLBCL may provide an efficient and targeted therapy. In screening for small-molecule compounds that may inhibit NF-κB activation in DLBCL cells, we identified a compound, NSC697923, which inhibits the activity of the ubiquitin-conjugating (E2) enzyme Ubc13-Uev1A. NSC697923 impedes the formation of the Ubc13 and ubiquitin thioester conjugate and suppresses constitutive NF-κB activity in ABC-DLBCL cells. Importantly, NSC697923 inhibits the proliferation and survival of ABC-DLBCL cells and GCB-DLBCL cells, suggesting the Ubc13-Uev1A may be crucial for DLBCL growth. Consistently, knockdown of Ubc13 expression also inhibited DLBCL cell survival. The results of the present study indicate that Ubc13-Uev1A may represent a potential therapeutic target in DLBCL. In addition, compound NSC697923 may be exploited for the development of DLBCL therapeutic agents.
弥漫性大 B 细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，仍然是一种部分可治愈的疾病。影响 NF-κB 信号通路组成部分的遗传改变在 DLBCL 中经常发生。几乎所有激活的 B 细胞样（ABC）DLBCL，这是这种恶性肿瘤的 3 个主要亚型中最不易治愈的一组，以及相当一部分生发中心 B 细胞样（GCB）DLBCL 表现出组成性 NF-κB 途径活性。已经证明 ABC-DLBCL 细胞需要这种活性才能增殖和存活。因此，抑制 DLBCL 中的 NF-κB 激活可能提供一种有效和靶向的治疗方法。在筛选可能抑制 DLBCL 细胞中 NF-κB 激活的小分子化合物时，我们鉴定出一种化合物 NSC697923，它抑制泛素缀合（E2）酶 Ubc13-Uev1A 的活性。NSC697923 阻碍 Ubc13 和泛素硫酯的形成，并抑制 ABC-DLBCL 细胞中的组成性 NF-κB 活性。重要的是，NSC697923 抑制 ABC-DLBCL 细胞和 GCB-DLBCL 细胞的增殖和存活，表明 Ubc13-Uev1A 可能对 DLBCL 的生长至关重要。一致地，Ubc13 表达的敲低也抑制了 DLBCL 细胞的存活。本研究的结果表明，Ubc13-Uev1A 可能代表 DLBCL 中的一个潜在治疗靶点。此外，化合物 NSC697923 可用于开发 DLBCL 治疗剂。
