BCL11B-Mediated Epigenetic Repression Is a Crucial Target for Histone Deacetylase Inhibitors in Cutaneous T-Cell Lymphoma
BCL11B-Mediated Epigenetic Repression Is a Crucial Target for Histone Deacetylase Inhibitors in Cutaneous T-Cell Lymphoma
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BCL11B 介导的表观遗传抑制是组蛋白脱乙酰酶抑制剂治疗皮肤 T 细胞淋巴瘤的关键靶点
DOI：
10.1016/j.jid.2017.02.980
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发表时间：
2017-07-01
影响因子：
6.5
通讯作者：
Wang, Yang
中科院分区：
文献类型：
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作者：
Fu, Wenjing;Yi, Shengguo;Wang, Yang
由于发病机制尚不清楚，晚期皮肤 T 细胞淋巴瘤 (CTCL) 的治疗选择受到限制。组蛋白脱乙酰酶 (HDAC) 抑制剂 (HDACis) 是最近开发的治疗难治性 CTCL 的药物。然而，响应率相对较低且不可预测。此前，我们发现与良性炎症皮肤相比，BCL11B（一种关键的 T 细胞发育调节因子）在蕈样肉芽肿（最常见的 CTCL）中异常过度表达。在这项研究中，我们发现 CTCL 细胞系中 BCL11B 表达与 HDACi 敏感性之间呈正相关。 BCL11B 高细胞中的 BCL11B 抑制通过去抑制细胞凋亡途径诱导细胞凋亡，并与泛 HDACi 辛二酰苯胺异羟肟酸 (SAHA) 表现出协同作用。接下来，我们确定了 CTCL 系中 BCL11B 和 HDAC1/2 之间的物理相互作用和共享下游基因。这种相互作用对于 BCL11B 的抗凋亡作用以及 BCL11B 抑制和 HDACi 治疗之间的协同作用至关重要。此外，在 46 名蕈样肉芽肿患者的临床样本中，BCL11B 在晚期肿瘤阶段表现出增加但变化的表达。对四名接受 SAHA 治疗的患者的分析表明，BCL11B 表达与 SAHA 治疗的良好反应之间呈正相关。总之，BCL11B 可以作为治疗靶点和提高晚期 CTCL 中 HDACi 疗效的有用标志物。
The treatment options for advanced cutaneous T-cell lymphoma (CTCL) are limited because of its unclear pathogenesis. Histone deacetylase (HDAC) inhibitors (HDACis) are recently developed therapeutics approved for refractory CTCL. However, the response rate is relatively low and unpredictable. Previously, we discovered that BCL11B, a key T-cell development regulator, was aberrantly overexpressed in mycosis fungoides, the most common CTCL, as compared with benign inflammatory skin. In this study, we identified a positive correlation between BCL11B expression and sensitivity to HDACi in CTCL lines. BCL11B suppression in BCL11B-high cells induced cell apoptosis by de-repressing apoptotic pathways and showed synergistic effects with suberoylanilide hydroxamic acid (SAHA), a pan-HDACi. Next, we identified the physical interaction and shared downstream genes between BCL11B and HDAC1/2 in CTCL lines. This interaction was essential in the antiapoptosis effect of BCL11B, and the synergism between BCL11B suppression and HDACi treatment. Further, in clinical samples from 46 mycosis fungoides patients, BCL11B showed increased but varied expression in advanced tumor stage. Analysis of four patients receiving SAHA treatment suggested a positive correlation between BCL11B expression and favorable response to SAHA treatment. In conclusion, BCL11B may serve as a therapeutic target and a useful marker for improving HDACi efficacy in advanced CTCL.