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

// Qin Zou 1 , Shi Tan 2 , Zailin Yang 3 , Juan Wang 4 , Jingrong Xian 1 , Shuaishuai Zhang 1 , Hongjun Jin 1 , Liyuan Yang 1 , Lu Wang 1 , Ling Zhang 1 1 Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China 2 Department of Clinical Laboratory, Chongqing Health Center for Women and Children, Chongqing, China 3 Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China 4 Children’s Medical Laboratory Diagnosis Center, Qilu Children’s Hospital of Shandong University, Jinan, China Correspondence to: Ling Zhang, email: lingzhang@cqmu.edu.cn Keywords: nucleophosmin 1, mutation, microRNA, leukemia, differentiation Received: May 30, 2016      Accepted: September 16, 2016      Published: September 23, 2016 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.