人类核仁磷酸蛋白1突变A通过调节miR-10b抑制白血病细胞的髓系分化。
The human nucleophosmin 1 mutation A inhibits myeloid differentiation of leukemia cells by modulating miR-10b.
作者信息
Zou Qin, Tan Shi, Yang Zailin, Wang Juan, Xian Jingrong, Zhang Shuaishuai, Jin Hongjun, Yang Liyuan, Wang Lu, Zhang Ling
机构信息
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Department of Clinical Laboratory, Chongqing Health Center for Women and Children, Chongqing, China.
出版信息
Oncotarget. 2016 Nov 1;7(44):71477-71490. doi: 10.18632/oncotarget.12216.
Mutations in the nucleophosmin 1 (NPM1) gene are the most frequent genetic alteration in acute myeloid leukemia (AML). Here, we showed that enforced expression of NPM1 mutation type A (NPM1-mA) inhibits myeloid differentiation of leukemia cells, whereas knockdown of NPM1-mA has the opposite effect. Our analyses of normal karyotype AML samples from The Cancer Genome Atlas (TCGA) dataset revealed that miR-10b is commonly overexpressed in NPM1-mutated AMLs. We also found high expression of miR-10b in primary NPM1-mutated AML blasts and NPM1-mA positive OCI-AML3 cells. In addition, NPM1-mA knockdown enhanced myeloid differentiation, while induced expression of miR-10b reversed this effect. Finally, we showed that KLF4 is downregulated in NPM1-mutated AMLs. These results demonstrated that miR-10b exerts its effects by repressing the translation of KLF4 and that NPM1-mA inhibits myeloid differentiation through the miR-10b/KLF4 axis. This sheds new light on the effect of NPM1 mutations' on leukemogenesis.
核磷蛋白1（NPM1）基因的突变是急性髓系白血病（AML）中最常见的基因改变。在此，我们发现强制表达NPM1突变A型（NPM1-mA）可抑制白血病细胞的髓系分化，而敲低NPM1-mA则有相反的效果。我们对来自癌症基因组图谱（TCGA）数据集的正常核型AML样本的分析显示，miR-10b在NPM1突变型AML中普遍过表达。我们还在原发性NPM1突变AML原始细胞和NPM1-mA阳性OCI-AML3细胞中发现了miR-10b的高表达。此外，敲低NPM1-mA可增强髓系分化，而诱导miR-10b表达则逆转了这种作用。最后，我们表明KLF4在NPM1突变型AML中表达下调。这些结果表明，miR-10b通过抑制KLF4的翻译发挥作用，并且NPM1-mA通过miR-10b/KLF4轴抑制髓系分化。这为NPM1突变对白血病发生的影响提供了新线索。
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