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.
Highlights
Acute myeloid leukemia (AML) arises from multiple, sequential genetic alterations
Consistent with previous reports revealing the capacity of PMA to induce myeloid differentiation in THP-1 cells, PMA treatment increased the expression of the myeloid-specific surface markers CD14 in THP-1 cells [26]
We demonstrated that nucleophosmin 1 (NPM1)-mA inhibited myeloid differentiation of leukemia cells in vitro, and that the miR-10b/KLF4 axis was involved in this process
Summary
Acute myeloid leukemia (AML) arises from multiple, sequential genetic alterations. Mutations in the nucleophosmin 1 (NPM1) gene are the most common, accounting for approximately one third of all adult de novo AML, especially in patients with normal karyotype AML (NK-AML) [1]. NPM1 is an abundant, multifunctional nucleolar protein with nuclear-cytoplasmic shuttling activity [2] and plays multiple roles in cell growth and proliferation [3, 4]. AML carrying NPM1 mutations is a distinct AML entity in the 2016 World Health Organization (WHO) classification of myeloid neoplasms because of its distinct biological and clinical features [5]. 60 different types of NPM1 mutations have been found, the most common being the type A mutation (NPM1-mA) with a four base (TCTG) insertion at exon 12 [4]. All molecular variants of NPM1 mutation result in changes at the C terminus of NPM1 that interfere with its nucleo-cytoplasmic traffic, giving rise to the aberrant cytoplasm-dislocated mutant NPM1
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