Abstract
Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations.
Highlights
Acute myeloid leukemia (AML) is a clinically and genomically heterogeneous malignancy despite having a relatively low number of genomic alterations compared to other cancers [1,2]
Our knowledge on the aberrant function of NPM1 mutations which lead to a unique leukemia has expanded
NPM1 mutations can be used as a robust biomarker indicating measurable residual disease (MRD)
Summary
Acute myeloid leukemia (AML) is a clinically and genomically heterogeneous malignancy despite having a relatively low number of genomic alterations compared to other cancers [1,2]. Treatment of AML had not changed in decades until recently, when several drugs received regulatory approval. This progress is largely due to an improved understanding of the biology and genomic landscape of this disease [4]. A mutation in the gene encoding nucleophosmin (NPM1) is one of the most commonly detected genomic alterations in AML. It is found in 20–30% of newly diagnosed AML and in 50% of those with a normal karyotype [1,5,6]. We summarize the current knowledge on the normal and aberrant functions of NPM1, highlight mechanisms of leukemogenesis and discuss rational therapeutic strategies
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