Author:
Yao Yiyi,Lin Xiangjie,Wang Chen,Gu Ying,Jin Jie,Zhu Yinghui,Wang Huafeng
Abstract
AbstractNucleophosmin (NPM1) is a widely expressed nucleocytoplasmic shuttling protein with prominent nucleolar localization. It is estimated that 25–35% of adult patients with acute myeloid leukemia (AML) carryNPM1mutations. The classicNPM1type A mutation occurs in exon 12, which accounts for 75–80% of adult patients withNPM1-mutated AML. It produces an additional leucine and valine-rich nuclear export signal (NES) at the C-terminus, and causes aberrant cytoplasmic dislocation of NPM1 protein. Notably, emerging evidence indicates that besides the classic type A mutation, rare mutants occurring in other exons may also lead to the imbalance of the nucleocytoplasmic shuttle of NPM1. Identification of novel non-type A mutants is crucial for the diagnosis, prognosis, risk stratification and disease monitoring of potential target populations. Here we reported a novelNPM1mutation in exon 5 identified from a de novo AML patient. Similar to the classic type A mutation, the exon 5 mutation had the NPM1 mutant bound to exportin-1 and directed the mutant into the cytoplasm by generating an additional NES sequence, resulting in aberrant cytoplasmic dislocation of NPM1 protein, which could be reversed by exportin-1 inhibitor leptomycin B. Our findings strongly support that besides the exon 12 mutation, the exon 5 mutant is anotherNPM1“born to be exported” mutant critical for leukemogenesis. Therefore, similar to the classic type A mutation, the identification of our novelNPM1mutation is beneficial for clinical laboratory diagnosis, genetic risk assessment and MRD monitoring.
Funder
2023 Science and Technology Innovation Plan of Shanghai Science and Technology Commission
the Fundamental Research Funds for the Central Universities
Natural Science Foundation of Zhejiang Province, China
Key research and development program of Zhejiang Province, China
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Hematology
Cited by
1 articles.
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