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NPM1 (nucleophosmin)

Written1997-12Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2001-08Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

Other namesB23
NPM
HGNC (Hugo) NPM1
LocusID (NCBI) 4869
Atlas_Id 22
Location 5q35.1
Location_base_pair Starts at 170814708 and ends at 170833731 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  NPM1 (5q35) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Fusion genes
(updated 2016)
ALK (2p23.2) / NPM1 (5q35.1)BSPRY (9q32) / NPM1 (5q35.1)FBXW11 (5q35.1) / NPM1 (5q35.1)
FERMT2 (14q22.1) / NPM1 (5q35.1)INPPL1 (11q13.4) / NPM1 (5q35.1)MLF1 (3q25.32) / NPM1 (5q35.1)
NPM1 (5q35.1) / ALK (2p23.2)NPM1 (5q35.1) / MLF1 (3q25.32)NPM1 (5q35.1) / NCL (2q37.1)
NPM1 (5q35.1) / PTMA (2q37.1)NPM1 (5q35.1) / RAB40B (17q25.3)NPM1 (5q35.1) / RAB4A (1q42.13)
NPM1 (5q35.1) / RARA (17q21.2)NPM1 (5q35.1) / TYK2 (19p13.2)RAB40B (17q25.3) / NPM1 (5q35.1)
RARA (17q21.2) / NPM1 (5q35.1)TXNRD1 (12q23.3) / NPM1 (5q35.1)

DNA/RNA

Description 11 exons on 25 kb;
Transcription in a centromeric --> telomeric orientation; transcription is cell-cycle regulated, reaching peaks at G1/S transition and being baseline at S/G2 1.6 kb mRNA

Protein

 
  DNA Diagram
Description 294 amino acids, 32.5 kDa; contains in C-term an oligomerization domain (residues 1-83), a metal binding site (residues 104-115) , 2 domains rich in acidic amino acids (residues 120- 132 and 161-188) , and 2 nuclear localisation signals in C-term; forms homo-hexameres; binds to single and double strand nucleic acids
Expression wide
Localisation nuclear, mainly in the nucleolus
Function RNA binding nucleolar phosphoprotein involved in preribosomal assembly; transport ribonucleoproteins between cellular compartments
Homology with nucleoplasmin

Implicated in

Note
Entity Anaplasic large cell lymphoma (ALCL) with t(2;5)(p23;q35) --> NPM1-ALK
Disease ALCL are high grade non Hodgkin lymphomas; ALK+ ALCL are ALCL where ALK is involved in a fusion gene; ALK+ ALCL represent 50 to 60 % of ALCL cases (they are CD30+, ALK+;); 80% of ALK+ ALCL cases bear a t(2;5)
Prognosis nonetheless, a 80% five yr survival may be associated with this anomaly
Cytogenetics additional anomalies are most often found
Hybrid/Mutated Gene 5' NPM1-3' ALK on der(5)
Abnormal Protein 680 amino acids, 80 kDa; N-term 116 amino acids from NPM1 fused to the 563 C-term aminoacids of ALK (i.e. composed of the oligomerization domain and the metal binding site of NPM1 ,and the entire cytoplasmic portion of ALK); no apparent expression of the ALK/NPM1 counterpart; Characteristic localisation both in the cytoplasm and in the nucleus, due to heterooligomerization of NPM-ALK and normal NPM whereas the normal NPM protein is confined to the nucleus; constitutive activation of the catalytic domain of ALK.
Oncogenesis via the kinase function activated by oligomerization of NPM1-ALK mediated by the NPM1 part
  
Entity t(3;5)(q25;q34)/in myeloid malignancies --> NPM - MLF1
Disease Acute non lymphocytic leukemia (AML), myelodysplasia (MDS), chronic myelogenous leukemia in blast crisis (BC-CML); trilineage involvement
Prognosis very poor
Cytogenetics location of breakpoints difficult to ascertain
Hybrid/Mutated Gene 5' NPM-3' MLF1 on der(5)
Abnormal Protein with the 175 N term amino acids of NPM1; nuclear protein
  
Entity t(5;17)(q34;q21)/M3-AML --> NPM1-RARa
Disease promyelocytic AML (M3-AML)
Cytogenetics variant translocation of the well known t(15;17)
Hybrid/Mutated Gene 5' NPM1-3' RARa on der(5)
Abnormal Protein with the 117 N term amino acids of NPM1
  

Breakpoints

 
 
Note within the 4th intron in the cases of t(2;5) or t(5;17), within the 6th intron in case of t(3;5)

Bibliography

Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT
Science (New York, N.Y.). 1994 ; 263 (5151) : 1281-1284.
PMID 8122112
 
The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1.
Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB, Raimondi SC, Cohen KJ, Carroll AJ, Morris SW
Oncogene. 1996 ; 12 (2) : 265-275.
PMID 8570204
 
The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion.
Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ
Blood. 1996 ; 87 (3) : 882-886.
PMID 8562957
 
The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion.
Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ
Blood. 1996 ; 87 (3) : 882-886.
PMID 8562957
 
Isolation and characterization of the human nucleophosmin/B23 (NPM) gene: identification of the YY1 binding site at the 5' enhancer region.
Chan PK, Chan FY, Morris SW, Xie Z
Nucleic acids research. 1997 ; 25 (6) : 1225-1232.
PMID 9092633
 
Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.
Bischof D, Pulford K, Mason DY, Morris SW
Molecular and cellular biology. 1997 ; 17 (4) : 2312-2325.
PMID 9121481
 
CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features.
Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B
Blood. 2000 ; 96 (12) : 3681-3695.
PMID 11090048
 
Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas.
Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 ; 14 (9) : 1533-1559.
PMID 10994999
 
Anaplastic large cell lymphomas, Primary systemic (T/Null cell type).
Delsol G, Ralfkiaer E, Stein H, Wright D, Jaffe E
World Health Organization (WHO) Classification of Tumors..
 
Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma.
Morris SW, Xue L, Ma Z, Kinney MC
British journal of haematology. 2001 ; 113 (2) : 275-295.
PMID 11380391
 

Citation

This paper should be referenced as such :
Huret, JL
NPM1 (nucleophosmin)
Atlas Genet Cytogenet Oncol Haematol. 2001;5(4):265-267.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NPM1ID22.html
History of this paper:
Huret, JL. NPM1 (nucleophosmin). Atlas Genet Cytogenet Oncol Haematol. 1997;1(2):70-71.
http://documents.irevues.inist.fr/bitstream/handle/2042/32058/12-1997-NPM1ID22.pdf


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 24 ]
  Anaplastic large cell lymphoma (ALCL)
Classification of myelodysplasic syndromes 1999
Chronic Myelomonocytic Leukemia (CMML)
i(17q) solely in myeloid malignancies
inv(2)(p23q35) ATIC/ALK
inv(3)(q21q26) RPN1/MECOM;t(3;3)(q21;q26) RPN1/MECOM;ins(3;3)(q26;q21q26) RPN1/MECOM
M3/M3v acute myeloid leukemia (AML M3/M3v);Acute promyelocytic leukemia (APL)
t(1;2)(q25;p23) TPM3/ALK
t(2;3)(p23;q21) TFG/ALK
t(2;5)(p23;q35) NPM1/ALK
t(2;5)(p23;q35) SQSTM1/ALK
t(2;17)(p23;q23) CLTC/ALK
t(2;17)(p23;q25) RNF213/ALK
t(2;22)(p23;q11) CLTCL1/ALK
t(2;22)(p23;q11) MYH9/ALK
t(3;5)(q25;q34) NPM1/MLF1
t(3;21)(q26;q22) RUNX1/MECOM
t(4;17)(q12;q21) FIP1L1/RARA
t(X;2)(q11;p23) MSN/ALK
t(11;17)(q23;q21) ZBTB16/RARA
t(11;17)(q13;q21) NUMA1/RARA
t(15;17)(q24;q21) PML/RARA
t(5;17)(q35;q21) NPM1/RARA
Classification of T-Cell disorders

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 0 ]
  Soft Tissues: Inflammatory myofibroblastic tumor with t(1;2)(q21;p23) TPM3/ALK

External links

Nomenclature
HGNC (Hugo)NPM1   7910
Cards
AtlasNPM1ID22
Entrez_Gene (NCBI)NPM1  4869  nucleophosmin (nucleolar phosphoprotein B23, numatrin)
GeneCards (Weizmann)NPM1
Ensembl hg19 (Hinxton)ENSG00000181163 [Gene_View]  chr5:170814708-170833731 [Contig_View]  NPM1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000181163 [Gene_View]  chr5:170814708-170833731 [Contig_View]  NPM1 [Vega]
ICGC DataPortalENSG00000181163
TCGA cBioPortalNPM1
AceView (NCBI)NPM1
Genatlas (Paris)NPM1
WikiGenes4869
SOURCE (Princeton)NPM1
Genomic and cartography
GoldenPath hg19 (UCSC)NPM1  -     chr5:170814708-170833731 +  5q35.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)NPM1  -     5q35.1   [Description]    (hg38-Dec_2013)
EnsemblNPM1 - 5q35.1 [CytoView hg19]  NPM1 - 5q35.1 [CytoView hg38]
Mapping of homologs : NCBINPM1 [Mapview hg19]  NPM1 [Mapview hg38]
OMIM164040   
Gene and transcription
Genbank (Entrez)AB042278 AB451236 AB451361 AI687394 AK000472
RefSeq transcript (Entrez)NM_001037738 NM_002520 NM_199185
RefSeq genomic (Entrez)NC_000005 NC_018916 NG_016018 NT_023133 NW_004929325
Consensus coding sequences : CCDS (NCBI)NPM1
Cluster EST : UnigeneHs.557550 [ NCBI ]
CGAP (NCI)Hs.557550
Alternative Splicing GalleryENSG00000181163
Gene ExpressionNPM1 [ NCBI-GEO ]   NPM1 [ EBI - ARRAY_EXPRESS ]   NPM1 [ SEEK ]   NPM1 [ MEM ]
Gene Expression Viewer (FireBrowse)NPM1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4869
GTEX Portal (Tissue expression)NPM1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP06748 (Uniprot)
NextProtP06748  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP06748
Splice isoforms : SwissVarP06748 (Swissvar)
PhosPhoSitePlusP06748
Domains : Interpro (EBI)NPM1_C    Nucleoplasmin    Nucleoplasmin_core_dom   
Domain families : Pfam (Sanger)NPM1-C (PF16276)   
Domain families : Pfam (NCBI)pfam16276   
DMDM Disease mutations4869
Blocks (Seattle)NPM1
PDB (SRS)2LLH    2P1B    2VXD   
PDB (PDBSum)2LLH    2P1B    2VXD   
PDB (IMB)2LLH    2P1B    2VXD   
PDB (RSDB)2LLH    2P1B    2VXD   
Structural Biology KnowledgeBase2LLH    2P1B    2VXD   
SCOP (Structural Classification of Proteins)2LLH    2P1B    2VXD   
CATH (Classification of proteins structures)2LLH    2P1B    2VXD   
SuperfamilyP06748
Human Protein AtlasENSG00000181163
Peptide AtlasP06748
HPRD01246
IPIIPI00549248   IPI00220740   IPI00604504   IPI00658013   IPI00985410   IPI00983818   
Protein Interaction databases
DIP (DOE-UCLA)P06748
IntAct (EBI)P06748
FunCoupENSG00000181163
BioGRIDNPM1
STRING (EMBL)NPM1
ZODIACNPM1
Ontologies - Pathways
QuickGOP06748
Ontology : AmiGOtranscription coactivator activity  RNA binding  protein kinase inhibitor activity  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytoplasm  cytoplasm  centrosome  centrosome  cytosol  focal adhesion  DNA repair  nucleosome assembly  intracellular protein transport  nucleocytoplasmic transport  nucleocytoplasmic transport  response to stress  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  centrosome cycle  centrosome cycle  signal transduction  cell aging  cell aging  protein localization  positive regulation of cell proliferation  negative regulation of cell proliferation  negative regulation of cell proliferation  negative regulation of centrosome duplication  membrane  viral process  protein kinase binding  intracellular ribonucleoprotein complex  Tat protein binding  spindle pole centrosome  regulation of endodeoxyribonuclease activity  CENP-A containing nucleosome assembly  ribosome assembly  histone binding  protein homodimerization activity  ribosomal large subunit binding  ribosomal small subunit binding  negative regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of protein kinase activity by regulation of protein phosphorylation  poly(A) RNA binding  positive regulation of translation  positive regulation of transcription, DNA-templated  regulation of centriole replication  protein heterodimerization activity  NF-kappaB binding  NF-kappaB binding  unfolded protein binding  unfolded protein binding  positive regulation of NF-kappaB transcription factor activity  protein oligomerization  regulation of endoribonuclease activity  regulation of eIF2 alpha phosphorylation by dsRNA  positive regulation of cell cycle G2/M phase transition  
Ontology : EGO-EBItranscription coactivator activity  RNA binding  protein kinase inhibitor activity  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytoplasm  cytoplasm  centrosome  centrosome  cytosol  focal adhesion  DNA repair  nucleosome assembly  intracellular protein transport  nucleocytoplasmic transport  nucleocytoplasmic transport  response to stress  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  centrosome cycle  centrosome cycle  signal transduction  cell aging  cell aging  protein localization  positive regulation of cell proliferation  negative regulation of cell proliferation  negative regulation of cell proliferation  negative regulation of centrosome duplication  membrane  viral process  protein kinase binding  intracellular ribonucleoprotein complex  Tat protein binding  spindle pole centrosome  regulation of endodeoxyribonuclease activity  CENP-A containing nucleosome assembly  ribosome assembly  histone binding  protein homodimerization activity  ribosomal large subunit binding  ribosomal small subunit binding  negative regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of protein kinase activity by regulation of protein phosphorylation  poly(A) RNA binding  positive regulation of translation  positive regulation of transcription, DNA-templated  regulation of centriole replication  protein heterodimerization activity  NF-kappaB binding  NF-kappaB binding  unfolded protein binding  unfolded protein binding  positive regulation of NF-kappaB transcription factor activity  protein oligomerization  regulation of endoribonuclease activity  regulation of eIF2 alpha phosphorylation by dsRNA  positive regulation of cell cycle G2/M phase transition  
REACTOMEP06748 [protein]
REACTOME PathwaysR-HSA-180746 Nuclear import of Rev protein [pathway]
REACTOME PathwaysR-HSA-606279 Deposition of new CENPA-containing nucleosomes at the centromere [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkNPM1
Wikipedia pathwaysNPM1
Orthology - Evolution
OrthoDB4869
GeneTree (enSembl)ENSG00000181163
Phylogenetic Trees/Animal Genes : TreeFamNPM1
Homologs : HomoloGeneNPM1
Homology/Alignments : Family Browser (UCSC)NPM1
Gene fusions - Rearrangements
Fusion : MitelmanBSPRY/NPM1 [9q32/5q35.1]  [t(5;9)(q35;q32)]  
Fusion : MitelmanNPM1/ALK [5q35.1/2p23.2]  [ins(5;2)(q35;p23p23)]  [t(2;5)(p23;q35)]  
Fusion : MitelmanNPM1/MLF1 [5q35.1/3q25.32]  [ins(3;5)(q25;q31q35)]  [t(3;5)(q25;q35)]  
Fusion : MitelmanNPM1/RAB4A [5q35.1/1q42.13]  [t(1;5)(q42;q35)]  
Fusion : MitelmanNPM1/RARA [5q35.1/17q21.2]  [t(11;17)(q23;q21)]  [t(15;17)(q22;q21)]  
[t(5;17)(q35;q21)]  
Fusion : MitelmanNPM1/TYK2 [5q35.1/19p13.2]  [t(5;19)(q35;p13)]  
Fusion : COSMICNPM1 [5q35.1]  -  ALK [2p23.2]  [fusion_198]  [fusion_199]  [fusion_200]  [fusion_201]  [fusion_420]  [fusion_448]  [fusion_449]  
[fusion_450]  [fusion_451]  [fusion_452]  [fusion_453]  [fusion_454]  [fusion_455]  [fusion_456]  [fusion_457]  [fusion_458]  
Fusion: TCGABSPRY 9q32 NPM1 5q35.1 BRCA
Fusion: TCGANPM1 5q35.1 RAB4A 1q42.13 BRCA
Fusion : TICdbNPM1 [5q35.1]  -  ALK [2p23.2]
Fusion : TICdbNPM1 [5q35.1]  -  MLF1 [3q25.32]
Fusion : TICdbNPM1 [5q35.1]  -  RARA [17q21.2]
Polymorphisms : SNP, variants
NCBI Variation ViewerNPM1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NPM1
dbVarNPM1
ClinVarNPM1
1000_GenomesNPM1 
Exome Variant ServerNPM1
ExAC (Exome Aggregation Consortium)NPM1 (select the gene name)
Genetic variants : HAPMAP4869
Genomic Variants (DGV)NPM1 [DGVbeta]
Mutations
ICGC Data PortalNPM1 
TCGA Data PortalNPM1 
Broad Tumor PortalNPM1
OASIS PortalNPM1 [ Somatic mutations - Copy number]
Cancer Gene: CensusNPM1 
Somatic Mutations in Cancer : COSMICNPM1 
intOGen PortalNPM1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NPM1
DgiDB (Drug Gene Interaction Database)NPM1
DoCM (Curated mutations)NPM1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NPM1 (select a term)
intoGenNPM1
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)5:170814708-170833731  ENSG00000181163
CONAN: Copy Number AnalysisNPM1 
Mutations and Diseases : HGMDNPM1
OMIM164040   
MedgenNPM1
Genetic Testing Registry NPM1
NextProtP06748 [Medical]
TSGene4869
GENETestsNPM1
Huge Navigator NPM1 [HugePedia]
snp3D : Map Gene to Disease4869
BioCentury BCIQNPM1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4869
Chemical/Pharm GKB GenePA31712
Clinical trialNPM1
Miscellaneous
canSAR (ICR)NPM1 (select the gene name)
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=NPM1
Probes
ProbeCancer Cytogenetics (Bari)
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNPM1
EVEXNPM1
GoPubMedNPM1
iHOPNPM1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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