Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia
Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia
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DOI：
10.1016/j.leukres.2007.03.012
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发表时间：
2007-10-01
影响因子：
2.7
通讯作者：
Liu, H. Eugene
中科院分区：
文献类型：
--
作者：
Cheng, Yun-Chih;Lin, Hsiupen;Liu, H. Eugene
丙戊酸（VPA）是一种治疗神经系统疾病的药物，已被证明是一类新的组蛋白去乙酰化酶抑制剂（HDACI），能够诱导急性髓性白血病（AML）的细胞凋亡和髓样分化。在这项研究中，我们研究了AML细胞中VPA介导活动的潜在机制。VIA不仅可使HL-60、U937和NB 4细胞生长停滞于G（0）/G（1）期，并引起细胞凋亡，还可引起细胞形态和表型的改变。VIA显著增加p21 WAF 1的表达，并在转录水平下调c-Myc表达。野生型c-Myc和T58 A突变体的异位表达显著抑制VPA介导的生长抑制。与细胞系研究的结果一样，VPA也下调c-Myc水平，并诱导原代AML细胞的凋亡和髓样分化，导致集落形成能力下降。鉴于c-Myc在白血病发生中的作用，我们的研究表明VPA可能是AML的潜在治疗药物。(c)2007爱思唯尔有限公司保留所有权利。
Valproic acid (VPA), an agent used for neurological disorders, has been shown to be a novel class of histone deacetylase inhibitor (HDACI), able to induce apoptosis and myeloid differentiation of acute myeloid leukemia (AML). In this study, we examined the underlying mechanisms in VPA-mediated activities in AML cells. VIA not only inhibited the growth of HL-60, U937 and NB4 cells by causing cell-cycle arrest at G(0)/G(1) phase and apoptosis, but also induced morphologic and phenotypic changes. VIA markedly increased p21 WAF1, and downregulated c-Myc expression at transcriptional levels. Ectopic expression of wildtype c-Myc and T58A mutant significantly inhibited VPA-mediated growth inhibition. As with results from cell line studies, VPA also downregulated c-Myc levels, and induced apoptosis and myeloid differentiation of primary AML cells, leading to decreased colony-forming ability. Given the role of c-Myc in leukemogenesis, our study suggests that VPA might be a potential therapeutic agent for AML. (c) 2007 Elsevier Ltd. All rights reserved.