Adult T-cell leukemia/lymphoma (ATL) is an intractable hematological malignancy with extremely poor prognosis. Recent studies have revealed that super-enhancers (SE) play important roles in controlling tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases including ATL. Cyclin-dependent protein kinase (CDK) 9 is a component of a complex comprising transcription factors (TFs) that bind the SE region. Alvocidib is a CDK9 inhibitor that exerts antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressing SE-mediated, tumor-specific gene expression. The present study demonstrated that alvocidib inhibited the proliferation of ATL cell lines and tumor cells from patients with ATL. RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) disclosed that SE regulated IRF4 in the ATL cell lines. Previous studies showed that IRF4 suppression inhibited ATL cell proliferation. Hence, IRF4 is a putative alvocidib target in ATL therapy. The present study revealed that SE-mediated IRF4 downregulation is a possible mechanism by which alvocidib inhibits ATL proliferation. Alvocidib also suppressed ATL in a mouse xenograft model. Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well.

中文翻译：

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Alvocidib 通过超增强子抑制和成人 T 细胞白血病/淋巴瘤细胞生长抑制 IRF4 表达

成人 T 细胞白血病/淋巴瘤 (ATL) 是一种顽固性血液系统恶性肿瘤，预后极差。最近的研究表明，超级增强子 (SE) 在控制肿瘤特异性基因表达方面发挥着重要作用，是包括 ATL 在内的肿瘤疾病的潜在治疗靶点。细胞周期蛋白依赖性蛋白激酶 (CDK) 9 是包含结合 SE 区域的转录因子 (TF) 的复合物的组成部分。Alvocidib 是一种 CDK9 抑制剂，通过抑制 RNA 聚合酶 (Pol) II 磷酸化和抑制 SE 介导的肿瘤特异性基因表达发挥抗肿瘤活性。本研究表明，alvocidib 可抑制 ATL 细胞系和 ATL 患者肿瘤细胞的增殖。RNA 测序 (RNA-Seq) 和染色质免疫沉淀测序 (ChIP-Seq) 表明 SE 调节 ATL 细胞系中的 IRF4。以前的研究表明 IRF4 抑制抑制 ATL 细胞增殖。因此，IRF4 是 ATL 治疗中推定的 alvocidib 靶标。本研究表明，SE 介导的IRF4下调是 alvocidib 抑制 ATL 增殖的一种可能机制。Alvocidib 还在小鼠异种移植模型中抑制 ATL。因此，目前的工作表明 alvocidib 对 ATL 具有治疗功效，并部分阐明了其作用方式。它还表明，alvocidib 有望用于 ATL 以及其他恶性肿瘤和肿瘤的临床治疗。