# NPM1

## Overview
NPM1 is a gene that encodes the nucleophosmin 1 protein, a multifunctional phosphoprotein primarily located in the nucleolus of eukaryotic cells. Nucleophosmin 1 is involved in a variety of cellular processes, including ribosome biogenesis, chromatin remodeling, and the regulation of the cell cycle. It functions as a molecular chaperone, assisting in the stabilization and localization of tumor suppressor proteins, and plays a critical role in DNA repair and centrosome duplication. Structurally, nucleophosmin 1 is characterized by its ability to form homopentamers, which is essential for its role in nucleolar organization and liquid-liquid phase separation. The protein's activity and interactions are modulated by post-translational modifications, such as phosphorylation. Mutations in the NPM1 gene are notably associated with acute myeloid leukemia (AML), where they lead to aberrant cytoplasmic localization of the protein, contributing to leukemogenesis (Falini2007Translocations; López2020Nucleophosmin).

## Structure
Nucleophosmin 1 (NPM1) is a multifunctional protein with a complex molecular structure. It consists of three main regions: the N-terminal core domain, a central linker, and the C-terminal domain. The N-terminal core domain is responsible for oligomerization, forming a symmetric pentamer of β-sandwiches with a jellyroll topology, which is highly conserved across the NPM family (López2020Nucleophosmin). This domain also contains leucine-rich nuclear export signals (NES) and is crucial for the protein's thermostable properties and molecular chaperone activity (Okuwaki2007The).

The central linker is an intrinsically disordered region (IDR) that connects the core to the C-terminal domain, contributing to the protein's flexibility and complicating structural determination (López2020Nucleophosmin). The C-terminal domain is composed of three α-helices and is relatively basic, allowing it to bind G-rich DNA sequences, including G-quadruplexes (López2020Nucleophosmin).

NPM1 undergoes post-translational modifications such as phosphorylation, which modulate its conformational flexibility and functionality (López2020Nucleophosmin). The protein exists in multiple splice variant isoforms, including B23.1 and B23.2, which differ by 35 amino acids at the C-terminal end (Okuwaki2007The). These structural features enable NPM1 to participate in various cellular processes, including nucleolar organization and DNA repair.

## Function
Nucleophosmin 1 (NPM1) is a multifunctional protein predominantly located in the nucleolus of healthy human cells, where it plays critical roles in ribosome biogenesis and cell growth. It is involved in the maturation and nuclear export of ribosomal subunits, acting as a chaperone to stabilize and localize tumor suppressor proteins such as p53 and ARF (López2020Nucleophosmin). NPM1 also participates in chromatin remodeling due to its histone chaperone abilities, contributing to nucleosome assembly and disassembly (Okuwaki2007The; López2020Nucleophosmin).

The protein is essential for centrosome duplication, a process regulated by its nuclear export signals, and is involved in the cellular stress response by accumulating misfolded proteins in the nucleolus (Okuwaki2007The; López2020Nucleophosmin). NPM1's role extends to DNA repair mechanisms, where it interacts with APE1, a key enzyme in the base excision repair pathway, enhancing its catalytic activity and contributing to genomic stability (López2020Nucleophosmin).

Structurally, NPM1 is a homopentamer with a β-structured core domain responsible for oligomerization, allowing it to engage in liquid-liquid phase separation, which is crucial for nucleolar organization (López2020Nucleophosmin). Its subcellular localization and function are regulated by post-translational modifications, including phosphorylation, which influences its interactions and activity during the cell cycle (Okuwaki2007The; López2020Nucleophosmin).

## Clinical Significance
Mutations in the NPM1 gene are significantly associated with acute myeloid leukemia (AML), particularly in cases with a normal karyotype, where they occur in approximately 20-35% of patients (Heath2017Biological; Verhaak2005Mutations). These mutations often result in the aberrant cytoplasmic localization of the NPM1 protein, a hallmark of NPM1-mutated AML (Falini2009Altered; Falini2007Translocations). NPM1 mutations are considered primary events in the pathogenesis of AML and are associated with a specific gene expression signature involving HOX and TALE genes (Verhaak2005Mutations). They are often found alongside other mutations such as FLT3-ITD and DNMT3A, which can influence prognosis and treatment strategies (Heath2017Biological; Sharma2023NPM).

In addition to AML, NPM1 mutations are rare in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS), but when present, they indicate a more aggressive disease course and a higher likelihood of progression to AML (Chen2020Nucleophosmin1). NPM1 is also implicated in other hematologic malignancies, such as anaplastic large-cell lymphoma (ALCL), where it forms fusion proteins that contribute to oncogenesis (Chen2020Nucleophosmin1). Overexpression of NPM1 is noted in various solid tumors and is linked to poor prognosis and drug resistance (Chen2020Nucleophosmin1).

## Interactions
Nucleophosmin 1 (NPM1) is a multifunctional protein that engages in various interactions with proteins and nucleic acids, playing a crucial role in cellular processes. NPM1 interacts with ribosomal subunit precursors, particularly the pre-60S ribosomal subunits, and is involved in their recruitment to specific cellular sites, contributing to nucleolar structure maintenance (Okuwaki2021The). It forms oligomers and interacts with proteins such as NCL, Lyar, BRIX1, and EBP2, which are involved in ribosomal subunit processing (Okuwaki2021The).

NPM1 also interacts with NF-κB proteins, specifically enhancing the DNA binding activity of the p65 and p50 subunits. This interaction is crucial for NF-κB-mediated transcription and gene expression, particularly in inflammation and immunity (Lin2016Efficient). NPM1 acts as a chaperone-like factor, facilitating the efficient binding of NF-κB to DNA without being part of the NF-κB/DNA complex (Lin2016Efficient).

In viral contexts, NPM1 interacts with HIV-1 Rev and HSV-1 US11 proteins. It binds to the N-terminal oligomerization domain and the central histone-binding domain, facilitating Rev's nucleolar localization and potentially affecting viral processes (Nouri2015Biophysical). These interactions highlight NPM1's role in both cellular and viral regulatory mechanisms.


## References


[1. (Chen2020Nucleophosmin1) Yingyu Chen and Jianda Hu. Nucleophosmin1 (npm1) abnormality in hematologic malignancies, and therapeutic targeting of mutant npm1 in acute myeloid leukemia. Therapeutic Advances in Hematology, 11:204062071989981, January 2020. URL: http://dx.doi.org/10.1177/2040620719899818, doi:10.1177/2040620719899818. This article has 28 citations and is from a peer-reviewed journal.](https://doi.org/10.1177/2040620719899818)

[2. (Nouri2015Biophysical) Kazem Nouri, Jens M. Moll, Lech-Gustav Milroy, Anika Hain, Radovan Dvorsky, Ehsan Amin, Michael Lenders, Luitgard Nagel-Steger, Sebastian Howe, Sander H. J. Smits, Hartmut Hengel, Lutz Schmitt, Carsten Münk, Luc Brunsveld, and Mohammad R. Ahmadian. Biophysical characterization of nucleophosmin interactions with human immunodeficiency virus rev and herpes simplex virus us11. PLOS ONE, 10(12):e0143634, December 2015. URL: http://dx.doi.org/10.1371/journal.pone.0143634, doi:10.1371/journal.pone.0143634. This article has 26 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0143634)

[3. (López2020Nucleophosmin) David J. López, José A. Rodríguez, and Sonia Bañuelos. Nucleophosmin, a multifunctional nucleolar organizer with a role in dna repair. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1868(12):140532, December 2020. URL: http://dx.doi.org/10.1016/j.bbapap.2020.140532, doi:10.1016/j.bbapap.2020.140532. This article has 31 citations.](https://doi.org/10.1016/j.bbapap.2020.140532)

[4. (Falini2009Altered) B Falini, N Bolli, A Liso, M P Martelli, R Mannucci, S Pileri, and I Nicoletti. Altered nucleophosmin transport in acute myeloid leukaemia with mutated npm1: molecular basis and clinical implications. Leukemia, 23(10):1731–1743, June 2009. URL: http://dx.doi.org/10.1038/leu.2009.124, doi:10.1038/leu.2009.124. This article has 176 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/leu.2009.124)

[5. (Okuwaki2007The) M. Okuwaki. The structure and functions of npm1/nucleophsmin/b23, a multifunctional nucleolar acidic protein. Journal of Biochemistry, 143(4):441–448, November 2007. URL: http://dx.doi.org/10.1093/JB/MVM222, doi:10.1093/jb/mvm222. This article has 284 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/JB/MVM222)

[6. (Lin2016Efficient) Jianhuang Lin, Mitsuyasu Kato, Kyosuke Nagata, and Mitsuru Okuwaki. Efficient dna binding of nf-κb requires the chaperone-like function of npm1. Nucleic Acids Research, pages gkw1285, December 2016. URL: http://dx.doi.org/10.1093/nar/gkw1285, doi:10.1093/nar/gkw1285. This article has 8 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkw1285)

[7. (Falini2007Translocations) B. Falini, I. Nicoletti, N. Bolli, M. P. Martelli, A. Liso, P. Gorello, F. Mandelli, C. Mecucci, and M. F. Martelli. Translocations and mutations involving the nucleophosmin (npm1) gene in lymphomas and leukemias. Haematologica, 92(4):519–532, April 2007. URL: http://dx.doi.org/10.3324/haematol.11007, doi:10.3324/haematol.11007. This article has 157 citations.](https://doi.org/10.3324/haematol.11007)

[8. (Sharma2023NPM) Naman Sharma and Jane L. Liesveld. Npm 1 mutations in aml—the landscape in 2023. Cancers, 15(4):1177, February 2023. URL: http://dx.doi.org/10.3390/cancers15041177, doi:10.3390/cancers15041177. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cancers15041177)

[9. (Okuwaki2021The) Mitsuru Okuwaki, Shoko Saito, Hiroko Hirawake-Mogi, and Kyosuke Nagata. The interaction between nucleophosmin/npm1 and the large ribosomal subunit precursors contribute to maintaining the nucleolar structure. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1868(1):118879, January 2021. URL: http://dx.doi.org/10.1016/j.bbamcr.2020.118879, doi:10.1016/j.bbamcr.2020.118879. This article has 17 citations.](https://doi.org/10.1016/j.bbamcr.2020.118879)

[10. (Heath2017Biological) E M Heath, S M Chan, M D Minden, T Murphy, L I Shlush, and A D Schimmer. Biological and clinical consequences of npm1 mutations in aml. Leukemia, 31(4):798–807, January 2017. URL: http://dx.doi.org/10.1038/leu.2017.30, doi:10.1038/leu.2017.30. This article has 128 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/leu.2017.30)

[11. (Verhaak2005Mutations) Roel G. W. Verhaak, Chantal S. Goudswaard, Wim van Putten, Maarten A. Bijl, Mathijs A. Sanders, Wendy Hugens, André G. Uitterlinden, Claudia A. J. Erpelinck, Ruud Delwel, Bob Löwenberg, and Peter J. M. Valk. Mutations in nucleophosmin (npm1) in acute myeloid leukemia (aml): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood, 106(12):3747–3754, December 2005. URL: http://dx.doi.org/10.1182/blood-2005-05-2168, doi:10.1182/blood-2005-05-2168. This article has 452 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2005-05-2168)