The human nucleophosmin 1 mutation A inhibits myeloid differentiation of leukemia cells by modulating miR-10b.

Abstract

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.

• Authors: Qin Zou, Shi Tan, Zailin Yang, Juan Wang, Jingrong Xian, Shuaishuai Zhang, Hongjun Jin, Liyuan Yang, Lu Wang, Ling Zhang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 44 Pg. 71477-71490 (Nov 01 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27669739 (Publication Type: Journal Article)

Chemical References

• KLF4 protein, human
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• MIRN10 microRNA, human
• MicroRNAs
• NPM1 protein, human
• Nuclear Proteins
• Nucleophosmin
• Tetradecanoylphorbol Acetate

Topics

• Adult
• Aged
• Cell Differentiation
• Female
• HL-60 Cells
• Humans
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics)
• Leukemia, Myeloid, Acute (genetics, pathology)
• Male
• MicroRNAs (physiology)
• Middle Aged
• Mutation
• Nuclear Proteins (genetics)
• Nucleophosmin
• Tetradecanoylphorbol Acetate (pharmacology)