Hes1 suppresses acute myeloid leukemia development through FLT3 repression
Hes1 suppresses acute myeloid leukemia development through FLT3 repression
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DOI：
10.1038/leu.2014.281
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发表时间：
2015-03-01
期刊：
影响因子：
11.4
通讯作者：
Chiba, S.
中科院分区：
文献类型：
--
作者：
Kato, T.;Sakata-Yanagimoto, M.;Chiba, S.
在白血病发生中，Notch信号传导可以以上下文依赖性的方式上调和下调。转录因子hairy和分裂增强子-1（Hes 1）被充分表征为Notch信号传导的下游靶标。Hes 1编码碱性螺旋-环-螺旋型蛋白，并抑制靶基因表达。在这里，我们报告说，删除Hes 1基因的小鼠促进急性髓细胞白血病（AML）的发展诱导的MLL-AF 9融合蛋白。然后我们发现Hes 1直接与FMS样酪氨酸激酶3（FLT 3）基因的启动子区结合，并下调启动子活性。因此，在表达MLL-AF 9的永生化和白血病细胞中，FLT 3在Hes 1或RBPJ无效背景下上调。表达MLL-AF 9的Hes 1缺失AML细胞在FLT 3配体刺激后显示出增强的增殖和ERK磷酸化。FLT 3抑制有效地消除了MLL-AF 9诱导的Hes 1缺失AML细胞的增殖。此外，激动性抗Notch 2抗体在Hes 1野生型背景下诱导MLL-AF 9诱导的AML细胞凋亡，但在Hes 1缺失背景下则不然。我们还访问了两个包含信使RNA（mRNA）表达谱的独立数据库，发现AML患者样本中FLT 3 mRNA的表达水平与HES 1的表达水平呈负相关。这些观察结果表明，Hes 1可能通过下调FLT 3表达介导Notch信号在AML发展中的肿瘤抑制作用。
In leukemogenesis, Notch signaling can be up and downregulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well-characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix-loop-helix-type protein, and represses target gene expression. Here, we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. FLT3 was consequently upregulated in MLL-AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing messenger RNA (mRNA) expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by downregulating FLT3 expression.