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NPM1-mutated acute myeloid leukemia: from bench to bedside
Brunangelo Falini1, Lorenzo Brunetti1, Paolo Sportoletti1
1Institute of Hematology, Centro Ricerche Emato-Oncologiche, Ospedale S. Maria della Misericordia, University of Perugia, Perugia, Italy.
Blood
|July 2, 2020
Summary
Mutations in the nucleophosmin (NPM1) gene are common in acute myeloid leukemia (AML), causing abnormal protein localization. Understanding NPM1
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- The nucleophosmin (NPM1) gene is crucial for cellular functions, with mutations being the most frequent genetic alteration in adult acute myeloid leukemia (AML).
- NPM1 mutations lead to aberrant cytoplasmic delocalization of the NPM1 protein, defining a distinct AML subtype.
- Wild-type NPM1 has recently identified nucleolar functions relevant to AML pathogenesis.
Purpose of the Study:
- To review recent findings on wild-type NPM1 functions and discuss biological and clinical aspects of NPM1-mutated AML.
- To explore the role of cooperating mutations, HOX gene expression, and clonal hematopoiesis in NPM1-mutated AML.
- To address diagnostic challenges, risk stratification, measurable residual disease (MRD) assessment, and emerging therapies for NPM1-mutated AML.
Main Methods:
- Literature review and synthesis of current research on NPM1 in AML.
- Analysis of the impact of NPM1 mutations on protein localization and cellular function.
- Discussion of clinical implications, including WHO classification, risk stratification, MRD monitoring, and preclinical therapeutic strategies.
Main Results:
- NPM1 mutations are a hallmark of a distinct AML entity, influencing prognosis and treatment response.
- Cooperation with other genetic mutations and HOX gene dysregulation significantly impacts AML development and outcomes.
- Preleukemic clonal hematopoiesis can predispose to secondary AML.
- NPM1 mutations are critical for European LeukemiaNet risk stratification.
- NPM1-based MRD assessment is valuable but has limitations for treatment guidance.
Conclusions:
- NPM1-mutated AML is a unique entity requiring specific diagnostic and therapeutic considerations.
- Eradication of NPM1-mutated clones is essential for achieving a cure.
- Targeting pathways involving XPO1 and menin-MLL shows promise in preclinical studies for NPM1-mutated AML.
- Further research is needed to address diagnostic ambiguities and optimize MRD monitoring.
