The human nucleophosmin 1 mutation A inhibits myeloid differentiation of leukemia cells by modulating miR-10b.
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.
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Qin
Q
Zou
Department of Clinical Laboratory, Chongqing Health Center for Women and Children, Chongqing, China.
Shi
S
Tan
Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
Zailin
Z
Yang
Children's Medical Laboratory Diagnosis Center, Qilu Children's Hospital of Shandong University, Jinan, China.
Juan
J
Wang
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Jingrong
J
Xian
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Shuaishuai
S
Zhang
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Hongjun
H
Jin
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Liyuan
L
Yang
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Lu
L
Wang
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Ling
L
Zhang
D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C547183:MIRN10 microRNA, human; D035683:MicroRNAs; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D013755:Tetradecanoylphorbol Acetate
differentiation; leukemia; microRNA; mutation; nucleophosmin 1
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