Abstract

Simple SummaryNucleophosmin (NPM1) protein regulates several cellular processes and is predominantly located in the nucleolus, owing to the localization signal provided by two tryptophan residues. In acute myeloid leukemia (AML), NPM1 gene is frequently mutated, leading to the aberrant translocation of the protein into cytoplasm. In the present work, we classified NPM1 mutations according to the loss of either one or both tryptophan residues as non-A-like and A-like mutations, respectively, and evaluated their biological features. We found that non-A-like mutations partially delocalize NPM1 protein into the cytoplasm, with a proportion of remaining nucleolar protein preserving p53 protein expression and downstream activity. Different HOXA and HOXB gene expression and cell death pathway activation between A-like and non-A-like NPM1-mutated cells were shown, with an enhanced sensitivity to chemotherapy for AML cells with non-A-like mutations. This study suggests the need for a sub-classification of NPM1-mutated AML, with subsequent implications in the therapeutic management.Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling protein, predominantly located in the nucleolus, that regulates a multiplicity of different biological processes. NPM1 localization in the cell is finely tuned by specific signal motifs, with two tryptophan residues (Trp) being essential for the nucleolar localization. In acute myeloid leukemia (AML), several NPM1 mutations have been reported, all resulting in cytoplasmic delocalization, but the putative biological and clinical significance of different variants are still debated. We explored HOXA and HOXB gene expression profile in AML patients and found a differential expression between NPM1 mutations inducing the loss of two (A-like) Trp residues and those determining the loss of one Trp residue (non-A-like). We thus expressed NPM1 A-like- or non-A-like-mutated vectors in AML cell lines finding that NPM1 partially remained in the nucleolus in the non-A-like NPM1-mutated cells. As a result, only in A-like-mutated cells we detected HOXA5, HOXA10, and HOXB5 hyper-expression and p14ARF/p21/p53 pathway deregulation, leading to reduced sensitivity to the treatment with either chemotherapy or Venetoclax, as compared to non-A-like cells. Overall, we identified that the NPM1 mutational status mediates crucial biological characteristics of AML cells, providing the basis for further sub-classification and, potentially, management of this subgroup of patients.

Highlights

  • Nucleophosmin (NPM1) is a multifunctional, nucleocytoplasmic shuttling protein, that shows a predominant nucleolar localization [1,2]

  • We explored HOXA and HOXB gene expression profile in acute myeloid leukemia (AML) patients and found a differential expression between NPM1 mutations inducing the loss of two (A-like) tryptophan residues (Trp) residues and those determining the loss of one Trp residue

  • We confirmed that NPM1wt was physiologically located into nucleolous and that NPM1mutA, NPM1mutB, and NPM1mutD were predominantly expressed in the cytoplasm

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Summary

Introduction

Nucleophosmin (NPM1) is a multifunctional, nucleocytoplasmic shuttling protein, that shows a predominant nucleolar localization [1,2]. NPM1 allows the correct localization of p14ARF in the nucleolus: in presence of an oncogenic stress, it triggers the activation of the p14ARF-p53 pro-apoptotic pathway, promoting MDM2 degradation, which, in turn, increases the stability of p53 and the levels of its downstream targets, such as p21. These mechanisms converge in regulating apoptosis [5]. The overexpression of NPM1 prevents the mitochondrial translocation of p53, necessary for the release of cytochrome C and the initiation of the intrinsic pathway of apoptosis [7]

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