NPM1 mutational status underlines different biological features in pediatric AML
| Autor: | Giulia Borella, Ambra Da Ros, Davide Padrin, Anna Marchetti, Elena Porcù, Claudia Tregnago, Martina Pigazzi, Katia Polato, Francesca Del Bufalo, Cristina Mecucci, Maddalena Benetton, Franco Locatelli |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research NPM1 Nucleolus Cell Biology medicine.disease_cause Article HOX genes Nucleophosmin NPM1 TP53 acute myeloid leukemia drug treatment gene expression genetic mutation 03 medical and health sciences chemistry.chemical_compound Drug treatment 0302 clinical medicine p14arf Genetic medicine RC254-282 Acute myeloid leukemia Gene expression Mutation Nucleophosmin Venetoclax Neoplasms. Tumors. Oncology. Including cancer and carcinogens Myeloid leukemia 030104 developmental biology medicine.anatomical_structure Oncology chemistry Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | Cancers Volume 13 Issue 14 Cancers, Vol 13, Iss 3457, p 3457 (2021) |
| Popis: | Simple Summary Nucleophosmin (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. Abstract 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. |
| Databáze: | OpenAIRE |
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