靶向 HTLV-I 调节的 BATF3/IRF4 转录网络治疗成人 T 细胞白血病/淋巴瘤。
Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma.
机构信息
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido 060-8638, Japan.
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
出版信息
Cancer Cell. 2018 Aug 13;34(2):286-297.e10. doi: 10.1016/j.ccell.2018.06.014. Epub 2018 Jul 26.
Adult T cell leukemia/lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). RNAi screening of ATLL lines revealed that their proliferation depends on BATF3 and IRF4, which cooperatively drive ATLL-specific gene expression. HBZ, the only HTLV-I encoded transcription factor that is expressed in all ATLL cases, binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including MYC. Inhibitors of bromodomain-and-extra-terminal-domain (BET) chromatin proteins collapsed the transcriptional network directed by HBZ and BATF3, and were consequently toxic for ATLL cell lines, patient samples, and xenografts. Our study demonstrates that the HTLV-I oncogenic retrovirus exploits a regulatory module that can be attacked therapeutically with BET inhibitors.
成人 T 细胞白血病/淋巴瘤（ATLL）是一种常无法治愈的疾病，与人类嗜 T 淋巴细胞病毒 I 型（HTLV-I）有关。对 ATLL 系的 RNAi 筛选表明，其增殖依赖于 BATF3 和 IRF4，它们共同驱动 ATLL 特异性基因表达。HBZ 是唯一在所有 ATLL 病例中表达的 HTLV-I 编码转录因子，它与 ATLL 特异性 BATF3 超级增强子结合，从而调节 BATF3 及其下游靶标（包括 MYC）的表达。溴结构域和末端结构域（BET）染色质蛋白抑制剂破坏了由 HBZ 和 BATF3 介导的转录网络，因此对 ATLL 细胞系、患者样本和异种移植物有毒。我们的研究表明，HTLV-I 致癌逆转录病毒利用了一个可以通过 BET 抑制剂进行治疗性攻击的调节模块。
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