NPM1

Nucleophosmin (nucleolar phosphoprotein B23, numatrin)
File:PBB Protein NPM1 image.jpg PDB rendering based on 2p1b.
Available structures PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB List of PDB id codes 2p1b​
Identifiers
Symbols	NPM1 ; B23; MGC104254; NPM
External IDs	Template:OMIM5 Template:MGI HomoloGene: 87629
Gene ontology Molecular function Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Cellular component Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Biological process Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO
RNA expression pattern
File:PBB GE NPM1 221691 x at tn.png
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

Nucleophosmin (nucleolar phosphoprotein B23, numatrin), also known as NPM1, is a human protein and gene. It has attracted recent attention as a prognostic indicator in cytogenetically normal Acute Myelocytic Leukemia (CN-AML). The NPM1-mutated AML encompasses all FAB / WHO catagories except FAB M3 (APL). NPM1 gene mutations are found only in primary AML and not in AML arising from myelodysplasia (MDS; secondary AML). NPM1 gene mutations are most common in AMLs with monocytic differentiation (FAB M4/M5). NPM1 mutations have a distinctive gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. NPM1 mutated AML is preferentially associated with AML with monocytic differentiation (inparticular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations and a trend toward a favorable clinical outcome especially in patients without the FLT3 gene mutation. NOM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM.

Genetics; The prevalence of cytogenetically-normal AML (CN-AML) varies between 40-49% of adults with de novo AML. Over half of the CN-AML patients can have the NPM1 mutation. The NPM1 gene is mapped to chromosome 5q15. NPM1 mutations cause alterations in the encoded protein that lead to its aberrant cytoplasmic localization. Mutations in nucleophosmin NPM1 are the most frequently ACQUIRED molecular abnormality in AML. NPM1 mutations positively correlate with AML with a high WBC count, normal karyotype and fms-tyrosine kinase 3 gene (FLT3) internal tandem duplication (ITD)mutations. FLT3ITD is a secondary genetic alteration that is not stable over the course of the disease. It is thoguht that the FLT3 "nullifies" the increased survival brought on by the presence of the NPM1. These mutations may contribute to leukemogenesis at least in part through disruption of the MDM2-p53 pathway and centrosome duplication.

CN-AML can be divided into two subsets; one is a molecular low risk group (ie CN-AML with NPM1 and NO FLT3ITD) which has a better outcome and the other is the molecular high risk group (ie patients with FLT3ITD or those without FLT3ITD and WITH wild-type, non-mutated NPM1). The event free survival (EFS) at 5 years is ~50% in patients with FLT3ITD negative / NPM1 mutated and only ~25% in patients with FLT3ITD positive / NPM1 wild-type (wt). The former have been considered to be a molecular low risk group and the latter a molecular high risk group. It has been shown that intermediate cytogenetic risk AML patient without FLT3ITD mutations but with NPM1 mutations have a significant better overall survival (OS) and EFS than those without NPM1 mutations. In multivariate analyses NPM1 mutations express an independent prognostic value with regeard to OS, EFS and disease free survival (DFS). In CN-AML patients older than 60 years the NPM1 mutation showed a higher complete response rate (CR) and had a significant increase in the OS compared with wild-type patients (84% versus 48%).

Patients who have NPM1 and lack FLT3ITD also have a high expression of a gene called ERG and have a negative outcome similar to molecular high risk patients. In contrast, patients who have NPM1+ and lack FLT3ITD would have a very favorable outcome if they express low levels of ERG.

Mechanism; The various NPM1 mutations identified in AML are heterozygous and involve the C-terminal region encoded by exon 12. These not only disrupt key tryptophan residues that are required for localization to the nucleolus, but also generate a nuclear export signal leading to delocalization of mutant NPM1 to the cytoplasm where it sequesters residual wild-type protein from the nucleus. It is also thought to play an important role in centrosome assembly and has RNA binding and chaperone activity. NPM1-mutated AMLs frequently have CD34-negative blasts, normal karyotype and have a good response to induction treatment. NPM1 is predominantly localized in the nucleolus and is thought to function as a molecular chaperone of proteins, facilitating the transport of ribosomal proteins through the nuclear membrane. Disruption of NPM1, either by chromosomal translocation or b mutation, results in the cytoplasmic dislocation of NPM1. The high frequency of NPM1 mutations in AML with normal karyotypes and the observation that cytoplasmic NPM1 cannot exert its normal function as binding partner and transporter protein leads to the notion that NPM1 mutation may be an early event in leukemogenesis. Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor suppressor pathway. Tranlocations involving the NPM gene cause cytoplasmic dislocation of the NPM protien.

The granulocytic, monocytic, erythroid and megakaryocytic series were found to be involved and these findings are consistent with the NPM1 mutation arising in myeloid or multipotent progenitors and raise the distinct possibility that this may be a primary lesion in AML, present in the leukemic stem cell population. NPM1-mutated / FLT3-ITD negative cases show a better prognosis (overall response and better response to induction treatment) reinforcing the concept that NPM1 mutation is a founder genetic lesion. Moreover, in cases where NPM1 and FLT3 are both mutated, multiple FLT3 internal tandem duplications (ITDs) can be detected within the leukemic subpopulations on the background of a single NPM1 mutation, implying that the latter was the first lesion to arise. A high frequency of NPM1 gene mutations are found in blasts that have a prominent nuclear invagination, a so-called 'cup-like' nuclei.

Chimeric oncoproteins generated as a result of the recurrent cytogenetic abnoramlities include t(8;21) / AML1-ETO, inv(16) / CBFB-MYH11 and t(11;23) / MLL rearrangements. The internal tandem duplication (ITD) in the fms-like tyrosine kinase-3 gene (FLT3) and the partial tandem duplication (PTD) of the mixed lineage leukemia gene (MLL) are indicative of a poor prognosis.

Immunopehnotypic analysis by flow cytometry has shown frequent absence of hematopoietic stem cell markers (CD34 and CD133) in NPM1-mutated AML (~80% versus 40% of cases lacking CD34 in NPM1-unmutated AML) while retaining other myeloid antigen markers such as CD13 and CD33. NPM1 mutations are a sensitive marker for minimal residual disease.

With regards to bone marrow transplantation if a patient had mutant NPM1 without FLT3ITD then there was no apparent advantage for transplantation in the first remission because, by analysis, for patients with NPM1-mutated / FLT3 wild-type, the relapse free survival (RFS) was the same regardless of whether or not a donor was available. If the patient had any genotype other than NPM1-mutated / FLT-wild type there was a definite benefit to receiving the allogeneic transplantation or at least having the donor and the potential for transplantation while in first remission.

Further reading

• Li L, Li HS, Pauza CD; et al. (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Gjerset RA (2007). "DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer". J. Mol. Histol. 37 (5–7): 239–51. doi:10.1007/s10735-006-9040-y. PMID 16855788.
• Chen W, Rassidakis GZ, Medeiros LJ (2006). "Nucleophosmin gene mutations in acute myeloid leukemia". Arch. Pathol. Lab. Med. 130 (11): 1687–92. PMID 17076533.CS1 maint: Multiple names: authors list (link)
• Falini B, Nicoletti I, Bolli N; et al. (2007). "Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias". Haematologica. 92 (4): 519–32. PMID 17488663.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Fankhauser C, Izaurralde E, Adachi Y; et al. (1991). "Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element". Mol. Cell. Biol. 11 (5): 2567–75. PMID 2017166.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Venkatesh LK, Mohammed S, Chinnadurai G (1990). "Functional domains of the HIV-1 rev gene required for trans-regulation and subcellular localization". Virology. 176 (1): 39–47. PMID 2109912.CS1 maint: Multiple names: authors list (link)
• Cochrane AW, Perkins A, Rosen CA (1990). "Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function". J. Virol. 64 (2): 881–5. PMID 2404140.CS1 maint: Multiple names: authors list (link)
• Chan PK, Chan WY, Yung BY; et al. (1986). "Amino acid sequence of a specific antigenic peptide of protein B23". J. Biol. Chem. 261 (30): 14335–41. PMID 2429957.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Zhang XX, Thomis DC, Samuel CE (1989). "Isolation and characterization of a molecular cDNA clone of a human mRNA from interferon-treated cells encoding nucleolar protein B23, numatrin". Biochem. Biophys. Res. Commun. 164 (1): 176–84. PMID 2478125.CS1 maint: Multiple names: authors list (link)
• Hale TK, Mansfield BC (1990). "Nucleotide sequence of a cDNA clone representing a third allele of human protein B23". Nucleic Acids Res. 17 (23): 10112. PMID 2602120.
• Chan WY, Liu QR, Borjigin J; et al. (1989). "Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth". Biochemistry. 28 (3): 1033–9. PMID 2713355.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Li XZ, McNeilage LJ, Whittingham S (1989). "The nucleotide sequence of a human cDNA encoding the highly conserved nucleolar phosphoprotein B23". Biochem. Biophys. Res. Commun. 163 (1): 72–8. PMID 2775293.CS1 maint: Multiple names: authors list (link)
• Chan PK, Aldrich M, Cook RG, Busch H (1986). "Amino acid sequence of protein B23 phosphorylation site". J. Biol. Chem. 261 (4): 1868–72. PMID 3944116.CS1 maint: Multiple names: authors list (link)
• Bocker T, Bittinger A, Wieland W; et al. (1995). "In vitro and ex vivo expression of nucleolar proteins B23 and p120 in benign and malignant epithelial lesions of the prostate". Mod. Pathol. 8 (3): 226–31. PMID 7542384.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Dundr M, Leno GH, Hammarskjöld ML; et al. (1995). "The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein". J. Cell. Sci. 108 ( Pt 8): 2811–23. PMID 7593322.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Miyazaki Y, Takamatsu T, Nosaka T; et al. (1995). "The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23". Exp. Cell Res. 219 (1): 93–101. doi:10.1006/excr.1995.1209. PMID 7628555.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Szebeni A, Herrera JE, Olson MO (1995). "Interaction of nucleolar protein B23 with peptides related to nuclear localization signals". Biochemistry. 34 (25): 8037–42. PMID 7794916.CS1 maint: Multiple names: authors list (link)
• Kato S, Sekine S, Oh SW; et al. (1995). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–50. PMID 7821789.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Marasco WA, Szilvay AM, Kalland KH; et al. (1995). "Spatial association of HIV-1 tat protein and the nucleolar transport protein B23 in stably transfected Jurkat T-cells". Arch. Virol. 139 (1–2): 133–54. PMID 7826206.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Valdez BC, Perlaky L, Henning D; et al. (1994). "Identification of the nuclear and nucleolar localization signals of the protein p120. Interaction with translocation protein B23". J. Biol. Chem. 269 (38): 23776–83. PMID 8089149.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)