Journal
ONCOTARGET
Volume 7, Issue 44, Pages 71477-71490Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12216
Keywords
nucleophosmin 1; mutation; microRNA; leukemia; differentiation
Categories
Funding
- National Natural Science Foundation of China [81271913]
- Natural Science Foundation of CQ CSTC [cstc2013jcyjA10035]
- Technology Foundation for Selected Overseas Chinese Scholar, Ministry of Personnel of China [2013009]
- Graduate Fellowship in research innovation from the Chongqing Municipal Education Commission [CYS15134]
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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.
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