Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
Blood. 2010 Jan 13. doi: 10.1182/blood-2009-07-232231.
Adult T-cell leukemia (ATL) is a T-cell malignancy etiologically associated with human T-cell leukemia virus type 1 (HTLV-1). Twist, a highly conserved basic helix-loop-helix transcription factor, is a newly identified oncogene. However, there are no reports on Twist expression in ATL. To define the role of Twist in leukemogenesis of ATL, we examined its expression in T-cell lines and PBMC. HTLV-1-infected T-cell lines and ATL cells expressed high levels of Twist compared with uninfected T-cell lines and normal PBMC. Immunohistochemistry showed immunostaining for Twist in ATL cells in ATL lymph nodes and skin lesions. Infection of normal PBMC with HTLV-1 induced Twist expression. Induction of the viral protein Tax in a human T-cell line led to upregulation of Twist. Tax-induced Twist expression involved the NF-kappaB and CREB signaling pathways. Twist augmented Tax-mediated HTLV-1 LTR and NF-kappaB activation. Short interfering RNA against Twist inhibited cell growth of HTLV-1-infected T-cell lines and downregulation of Twist expression in an HTLV-1-infected T-cell line inhibited the expression of Akt1, interleukin-2 receptor alpha chain, and Tax as well as the known target genes of Twist, YB-1 and Akt2. In conclusion, the results suggest that Tax-induced induction of Twist contributes to leukemogenesis of ATL.
成人 T 细胞白血病（ATL）是一种与人类 T 细胞白血病病毒 1 型（HTLV-1）病因相关的 T 细胞恶性肿瘤。Twist 是一种高度保守的碱性螺旋-环-螺旋转录因子，是新发现的癌基因。然而，目前尚无关于 Twist 在 ATL 中表达的报道。为了明确 Twist 在 ATL 白血病发生中的作用，我们检测了其在 T 细胞系和 PBMC 中的表达。与未感染的 T 细胞系和正常 PBMC 相比，HTLV-1 感染的 T 细胞系和 ATL 细胞表达高水平的 Twist。免疫组化显示，ATL 淋巴结和皮肤病变中的 ATL 细胞存在 Twist 的免疫染色。正常 PBMC 感染 HTLV-1 可诱导 Twist 表达。人 T 细胞系中 Tax 蛋白的诱导导致 Twist 的上调。Tax 诱导的 Twist 表达涉及 NF-kappaB 和 CREB 信号通路。Twist 增强了 Tax 介导的 HTLV-1 LTR 和 NF-kappaB 激活。针对 Twist 的短发夹 RNA 抑制了 HTLV-1 感染的 T 细胞系的细胞生长，并且在 HTLV-1 感染的 T 细胞系中下调 Twist 表达抑制了 Akt1、白细胞介素-2 受体 alpha 链和 Tax 的表达以及 Twist 的已知靶基因 YB-1 和 Akt2。总之，结果表明 Tax 诱导的 Twist 诱导有助于 ATL 的白血病发生。
