JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms.
JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms.
复制标题
DOI：
10.18632/oncotarget.8836
复制
发表时间：
2016-05-17
期刊：
影响因子：
--
通讯作者：
Tan X
中科院分区：
文献类型：
--
作者：
Zhang Y;Shen L;Stupack DG;Bai N;Xun J;Ren G;Han J;Li L;Luo Y;Xiang R;Tan X
JMJD 3（Jumonji domain containing-3）是一种组蛋白H3 Lys 27（H3 K27）脱甲基酶，已报道其参与抗原驱动的生发中心B细胞分化。然而，对JMJD 3在DLBCL（弥漫性大B细胞淋巴瘤）进展中的机制的了解仍然很少。在这项研究中，我们研究了DLBCL中亚型特异性JMJD 3依赖性生存效应。我们的数据表明，在ABC亚型，沉默下来的JMJD 3抑制干扰素调节因子4（IRF 4）的表达在脱甲基酶活性依赖的方式。IRF 4 β刺激JMJD 3的表达，形成促进这些细胞存活的正反馈回路。因此，IRF 4表达足以挽救ABC中JMJD 3抑制的促凋亡作用，但在GCB亚型中不足以。相反，BCL-2的异位过表达完全抵消了GCB DLBCL细胞中JMJD 3介导的存活。在体内，用针对JMJD 3的siRNA治疗减少了肿瘤体积，这与任一亚型中细胞凋亡的增加一致。这表明它是一个共同的目标，尽管调节DCBCL生存的独特信号传导轴为治疗DLBCL亚型提供了不同的策略选择。
JMJD3 (Jumonji domain containing-3), a histone H3 Lys27 (H3K27) demethylase, has been reported to be involved in the antigen-driven differentiation of germinal center B-cells. However, insight into the mechanism of JMJD3 in DLBCL (Diffuse large B-cell lymphoma) progression remains poorly understood. In this study, we investigated the subtype-specific JMJD3-dependent survival effects in DLBCL. Our data showed that in the ABC subtype, silencing-down of JMJD3 inhibited interferon regulatory factor 4 (IRF4) expression in a demethylase activity-dependent fashion. IRF4 reciprocally stimulated expression of JMJD3, forming a positive feedback loop that promoted survival in these cells. Accordingly, IRF4 expression was sufficient to rescue the pro-apoptotic effect of JMJD3 suppression in the ABC, but not in the GCB subtype. In contrast, ectopic overexpression of BCL-2 completely offset JMJD3-mediated survival in the GCB DLBCL cells. In vivo, treatment with siRNA to JMJD3 reduced tumor volume concordant with increased apoptosis in either subtype. This suggests it is a common target, though the distinctive signaling axes regulating DCBCL survival offer different strategic options for treating DLBCL subtypes.
登录
查看更多内容
影响因子：
10.5
作者：
Barradas, Marta;Anderton, Emma;Gil, Jesus
通讯作者：
Gil, Jesus
影响因子：
56.9
作者：
Lenz, Georg;Davis, R. Eric;Staudt, Louis M.
通讯作者：
Staudt, Louis M.
体细胞突变改变生发中心起源的滤泡性和弥漫性大 B 细胞淋巴瘤中的 EZH2 (Tyr641)。
影响因子：
30.8
作者：
Morin, Ryan D.;Johnson, Nathalie A.;Severson, Tesa M.;Mungall, Andrew J.;An, Jianghong;Goya, Rodrigo;Paul, Jessica E.;Boyle, Merrill;Woolcock, Bruce W.;Kuchenbauer, Florian;Yap, Damian;Humphries, R. Keith;Griffith, Obi L.;Shah, Sohrab;Zhu, Henry;Kimbara, Michelle;Shashkin, Pavel;Charlot, Jean F.;Tcherpakov, Marianna;Corbett, Richard;Tam, Angela;Varhol, Richard;Smailus, Duane;Moksa, Michelle;Zhao, Yongjun;Delaney, Allen;Qian, Hong;Birol, Inanc;Schein, Jacqueline;Moore, Richard;Holt, Robert;Horsman, Doug E.;Connors, Joseph M.;Jones, Steven;Aparicio, Samuel;Hirst, Martin;Gascoyne, Randy D.;Marra, Marco A.
通讯作者：
Marra, Marco A.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
通讯作者：
Staudt, LM