The nucleophosmin (NPM1) gene encodes for a multifunctional protein with prominent nucleolar localization that shuttles between nucleus and cytoplasm. NPM1 mutations represent the most common genetic lesion in adult AML (about one-third of cases) and act deterministically to cause the aberrant cytoplasmic delocalization of NPM1 mutants. Because of its unique features, NPM1-mutated AML is recognized as a distinct entity in the 2016 World Health Organization classification of hematopoietic neoplasms. Here, we focus on recently identified functions of wild-type NPM1 in the nucleolus and address new biological and clinical issues on NPM1-mutated AML. The relevance of cooperation between NPM1 and other mutations in driving AML with different outcomes is presented. We also discuss the importance of eradicating NPM1-mutated clones to achieve AML cure and the impact of pre-leukemic clonal hematopoiesis persistence in predisposing to second AML. The contribution of HOX genes expression to the development of NPM1-mutated AML is also highlighted. Clinically, yet unsolved diagnostic issues in the 2016-WHO classification of myeloid neoplasms and the importance of NPM1 mutations in defining the framework of European LeukemiaNet genetic-based risk-stratification are discussed. Finally, we address the value and limits of NPM1-based minimal residual disease assessment for treatment guidance and present the results of promising preclinical studies with XPO1 and Menin-MLL inhibitors.

NPM1-mutated acute myeloid leukemia: from bench to bedside

Falini, Brunangelo
;
Brunetti, Lorenzo;Sportoletti, Paolo;Martelli, Maria Paola
2020

Abstract

The nucleophosmin (NPM1) gene encodes for a multifunctional protein with prominent nucleolar localization that shuttles between nucleus and cytoplasm. NPM1 mutations represent the most common genetic lesion in adult AML (about one-third of cases) and act deterministically to cause the aberrant cytoplasmic delocalization of NPM1 mutants. Because of its unique features, NPM1-mutated AML is recognized as a distinct entity in the 2016 World Health Organization classification of hematopoietic neoplasms. Here, we focus on recently identified functions of wild-type NPM1 in the nucleolus and address new biological and clinical issues on NPM1-mutated AML. The relevance of cooperation between NPM1 and other mutations in driving AML with different outcomes is presented. We also discuss the importance of eradicating NPM1-mutated clones to achieve AML cure and the impact of pre-leukemic clonal hematopoiesis persistence in predisposing to second AML. The contribution of HOX genes expression to the development of NPM1-mutated AML is also highlighted. Clinically, yet unsolved diagnostic issues in the 2016-WHO classification of myeloid neoplasms and the importance of NPM1 mutations in defining the framework of European LeukemiaNet genetic-based risk-stratification are discussed. Finally, we address the value and limits of NPM1-based minimal residual disease assessment for treatment guidance and present the results of promising preclinical studies with XPO1 and Menin-MLL inhibitors.
2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1475149
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