The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms.

Katalin Kelemen

doi:10.3390/life12010109

Abstract

Nucleophosmin (NPM1) is a multifunctional protein with both proliferative and growth-suppressive roles in the cell. In humans, NPM1 is involved in tumorigenesis via chromosomal translocations, deletions, or mutation. Acute myeloid leukemia (AML) with mutated NPM1, a distinct diagnostic entity by the current WHO Classification of myeloid neoplasm, represents the most common diagnostic subtype in AML and is associated with a favorable prognosis. The persistence of NPM1 mutation in AML at relapse makes this mutation an ideal target for minimal measurable disease (MRD) detection. The clinical implication of this is far-reaching because NPM1-mutated AML is currently classified as being of standard risk, with the best treatment strategy (transplantation versus chemotherapy) yet undefined. Myeloid neoplasms with NPM1 mutations and <20% blasts are characterized by an aggressive clinical course and a rapid progression to AML. The pathological classification of these cases remains controversial. Future studies will determine whether NPM1 gene mutation may be sufficient for diagnosing NPM1-mutated AML independent of the blast count. This review aims to summarize the role of NPM1 in normal cells and in human cancer and discusses its current role in clinical management of AML and related myeloid neoplasms.

Highlights

Nucleophosmin (NPM1), called B23 or numatrin, is a phosphoprotein expressed at high levels in the granular region of the nucleolus [1,2]
Nucleophosmin 1 (NPM1) is remarkable for its specificity to a subtype of acute myeloid leukemia (AML) that is recognized as a specific diagnostic entity by the current WHO classification of myeloid neoplasms
In addition to its role in diagnostic subclassification, NPM1 mutation determines a subgroup of AML with favorable prognosis, though this is influenced by the presence or absence of certain concomitant mutations, in particular FLT3-ITD and DNMT3

Summary

Introduction

Nucleophosmin (NPM1), called B23 or numatrin, is a phosphoprotein expressed at high levels in the granular region of the nucleolus [1,2]. By shuttling between cellular compartments, NPM1 participates in a multitude of cellular processes, including transport of pre-ribosomal particles, ribosome of two tryptophans at the C-terminus localized at W288 and W290, respectively [13,14] Through these various domains, NPM1 can interact with many partners, such as nucleolar factors (nucleolin, fibrillarin), transcription factors (interferon regulatory factor 1 (IRF1), nuclear factor kappa B (NFkB)), histones (H3, H4, and H2B), proteins and enzymes (DNA polymerase-alpha), proteins of mitosis (NUMA), and proteins that respond to oncog2eonfi1c5 stress (p53, ARF). NPM1 exists predominantly as an oligomer [19] and less commonly in the form of pentamers and decamers [20]

NPM1 in Human Cancer

Prognosis of NPM1-Mutated AML

Findings

Summary