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PML (Promyelocytic leukemia)

Identity

Other namesMYL (myelocytic leukemia)
HGNC (Hugo) PML
LocusID (NCBI) 5371
Location 15q24.1
Location_base_pair Starts at 74287014 and ends at 74335717 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics

DNA/RNA

Description 9 coding exons; total gene sequence: 35 kb ?
Transcription 3 main mRNAs 4.6, 3.0 and 2.1 kb; alternative splicing generates at least 16 isoforms of mRNAs, varying in the region coding for the C-terminal part of the protein

Protein

 
Description 560 amino acids, 70 KDa (longest isoform); composed successively, from the N- to the C-terminus, by: 1- a proline-rich N-terminus 2- a so-called "tripartite motif", cysteine-histidine rich, composed of a RING finger structure and 2 B box domains, with putative DNA-binding function 3- a coiled-coil motif corresponding to a dimerization interface 4- a basic sequence with a nuclear localization domain, and 5- a serine-proline rich C-terminal region, of unknown function, variable in length (alternative splicing) and containing phosphorylation sites
Expression in a wide variety of tissues. In hematopoietic tissue, expression apparently restricted to myeloid precursors
Localisation nuclear, as part of a multiproteic complex located into multiple subnuclear PML oncogenic domains (PODs)
Function unknown to date; putative transcription factor; in conjunction with other proteins included in the PODs, it would play a role as tumor suppressor and in apoptosis
Homology with (numerous) other RING finger / B box proteins

Implicated in

Entity t(15;17)(q22;q21) / acute promyelocytic leukemia (APL) -->PML- RARA
Disease typical APL (or M3 ANLL, FAB classification), approximately 98% of APL cases; abnormal promyelocytes with Auer rods and bundles (faggots); disruption of the PODs with a microspeckeled pattern; maturation response to all-trans retinoic acid (ATRA) therapy
Prognosis immediate prognosis impaired by intravascular disseminated coagulopathy; long term prognosis is favorable with treatment combining ATRA plus chemotherapy
Cytogenetics variant or complex t(15;17) translocation in 5% of cases, no known prognosis implication; secondary chromosomal abnormalities in 30 to 35% of APL at diagnosis; association with +8 in 17 to 28% of cases; other associations are rare but recurrent: del(7q), del(9q), ider(17)t(15;17), +21
Hybrid/Mutated Gene
  • the crucial fusion transcript is 5'PML-3'RARA, encoded by der(15) chromosome; the counterpart 5'RARA-3'PML encoded by der(17) is inconstant
  • breakpoint in RARA gene is always located in intron between A and B domains
  • three breakpoint clusters in PML gene: bcr1 (70% of patients), bcr2 (10%) and bcr3 (20%), giving rise respectively to the long (L), intermediate (V) and short (S) length hybrid PML-RARAtranscripts; V form would be linked to ATRA decreased sensitivity and S form to association with an excess of secondary chromosome changes.
  • Abnormal Protein 106 Kda fusion protein; role in the leukemogenic process by probable interference with the signalling pathway leading to differentiation and maturation of myeloid precursors (mainly dysregulation of retinoid-inducible genes involved in myeloid differentiation)
      

    Breakpoints

     

    External links

    Nomenclature
    HGNC (Hugo)PML   9113
    Cards
    AtlasPMLID41
    Entrez_Gene (NCBI)PML  5371  promyelocytic leukemia
    GeneCards (Weizmann)PML
    Ensembl (Hinxton)ENSG00000140464 [Gene_View]  chr15:74287014-74335717 [Contig_View]  PML [Vega]
    AceView (NCBI)PML
    Genatlas (Paris)PML
    WikiGenes5371
    SOURCE (Princeton)NM_002675 NM_033238 NM_033239 NM_033240 NM_033244 NM_033246 NM_033247 NM_033249 NM_033250
    Genomic and cartography
    GoldenPath (UCSC)PML  -  15q24.1   chr15:74287014-74335717 +  15q24.1   [Description]    (hg19-Feb_2009)
    EnsemblPML - 15q24.1 [CytoView]
    Mapping of homologs : NCBIPML [Mapview]
    OMIM102578   
    Gene and transcription
    Genbank (Entrez)AB208950 AB209051 AB209411 AF230401 AF230402
    RefSeq transcript (Entrez)NM_002675 NM_033238 NM_033239 NM_033240 NM_033244 NM_033246 NM_033247 NM_033249 NM_033250
    RefSeq genomic (Entrez)AC_000147 NC_000015 NC_018926 NG_029036 NT_010194 NW_001838218 NW_004929398
    Consensus coding sequences : CCDS (NCBI)PML
    Cluster EST : UnigeneHs.526464 [ NCBI ]
    CGAP (NCI)Hs.526464
    Alternative Splicing : Fast-db (Paris)GSHG0010001
    Alternative Splicing GalleryENSG00000140464
    Gene ExpressionPML [ NCBI-GEO ]     PML [ SEEK ]   PML [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP29590 (Uniprot)
    NextProtP29590  [Medical]
    With graphics : InterProP29590
    Splice isoforms : SwissVarP29590 (Swissvar)
    Domaine pattern : Prosite (Expaxy)ZF_BBOX (PS50119)    ZF_RING_1 (PS00518)    ZF_RING_2 (PS50089)   
    Domains : Interpro (EBI)DUF3583    Znf_B-box    Znf_RING    Znf_RING/FYVE/PHD    Znf_RING_CS   
    Related proteins : CluSTrP29590
    Domain families : Pfam (Sanger)DUF3583 (PF12126)    zf-B_box (PF00643)   
    Domain families : Pfam (NCBI)pfam12126    pfam00643   
    Domain families : Smart (EMBL)BBOX (SM00336)  RING (SM00184)  
    DMDM Disease mutations5371
    Blocks (Seattle)P29590
    PDB (SRS)1BOR   
    PDB (PDBSum)1BOR   
    PDB (IMB)1BOR   
    PDB (RSDB)1BOR   
    Human Protein AtlasENSG00000140464
    Peptide AtlasP29590
    HPRD00023
    IPIIPI00022348   IPI00973909   IPI00974373   IPI00974368   IPI00291097   IPI00395707   IPI00303999   IPI00304000   IPI00940182   IPI00220453   IPI00922350   IPI00922504   IPI00332110   IPI00744329   IPI01014866   IPI00382504   IPI00977694   IPI00395893   
    Protein Interaction databases
    DIP (DOE-UCLA)P29590
    IntAct (EBI)P29590
    FunCoupENSG00000140464
    BioGRIDPML
    InParanoidP29590
    Interologous Interaction database P29590
    IntegromeDBPML
    STRING (EMBL)PML
    Ontologies - Pathways
    Ontology : AmiGOresponse to hypoxia  regulation of protein phosphorylation  positive regulation of defense response to virus by host  DNA binding  transcription coactivator activity  protein binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  nucleolus  cytoplasm  cytosol  transcription, DNA-templated  regulation of transcription, DNA-dependent  protein complex assembly  protein targeting  protein targeting  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  cell cycle arrest  transforming growth factor beta receptor signaling pathway  common-partner SMAD protein phosphorylation  SMAD protein import into nucleus  zinc ion binding  zinc ion binding  negative regulation of cell proliferation  intrinsic apoptotic signaling pathway in response to DNA damage  response to UV  response to gamma radiation  regulation of calcium ion transport into cytosol  nuclear matrix  nuclear matrix  negative regulation of angiogenesis  PML body  PML body  PML body  modulation by virus of host morphology or physiology  cytokine-mediated signaling pathway  myeloid cell differentiation  negative regulation of cell growth  PML body organization  PML body organization  positive regulation of histone deacetylation  ubiquitin protein ligase binding  early endosome membrane  nuclear membrane  SUMO binding  negative regulation of telomere maintenance via telomerase  endoplasmic reticulum calcium ion homeostasis  negative regulation of translation in response to oxidative stress  response to cytokine  extrinsic to endoplasmic reticulum membrane  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  protein homodimerization activity  proteasome-mediated ubiquitin-dependent protein catabolic process  cell fate commitment  regulation of MHC class I biosynthetic process  negative regulation of transcription, DNA-dependent  negative regulation of mitotic cell cycle  SMAD binding  protein heterodimerization activity  retinoic acid receptor signaling pathway  protein stabilization  cobalt ion binding  maintenance of protein location in nucleus  defense response to virus  negative regulation of telomerase activity  positive regulation of apoptotic process involved in mammary gland involution  interferon-gamma-mediated signaling pathway  branching involved in mammary gland duct morphogenesis  cellular response to interleukin-4  cellular senescence  negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process  regulation of double-strand break repair  positive regulation of extrinsic apoptotic signaling pathway  
    Ontology : EGO-EBIresponse to hypoxia  regulation of protein phosphorylation  positive regulation of defense response to virus by host  DNA binding  transcription coactivator activity  protein binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  nucleolus  cytoplasm  cytosol  transcription, DNA-templated  regulation of transcription, DNA-dependent  protein complex assembly  protein targeting  protein targeting  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  cell cycle arrest  transforming growth factor beta receptor signaling pathway  common-partner SMAD protein phosphorylation  SMAD protein import into nucleus  zinc ion binding  zinc ion binding  negative regulation of cell proliferation  intrinsic apoptotic signaling pathway in response to DNA damage  response to UV  response to gamma radiation  regulation of calcium ion transport into cytosol  nuclear matrix  nuclear matrix  negative regulation of angiogenesis  PML body  PML body  PML body  modulation by virus of host morphology or physiology  cytokine-mediated signaling pathway  myeloid cell differentiation  negative regulation of cell growth  PML body organization  PML body organization  positive regulation of histone deacetylation  ubiquitin protein ligase binding  early endosome membrane  nuclear membrane  SUMO binding  negative regulation of telomere maintenance via telomerase  endoplasmic reticulum calcium ion homeostasis  negative regulation of translation in response to oxidative stress  response to cytokine  extrinsic to endoplasmic reticulum membrane  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  protein homodimerization activity  proteasome-mediated ubiquitin-dependent protein catabolic process  cell fate commitment  regulation of MHC class I biosynthetic process  negative regulation of transcription, DNA-dependent  negative regulation of mitotic cell cycle  SMAD binding  protein heterodimerization activity  retinoic acid receptor signaling pathway  protein stabilization  cobalt ion binding  maintenance of protein location in nucleus  defense response to virus  negative regulation of telomerase activity  positive regulation of apoptotic process involved in mammary gland involution  interferon-gamma-mediated signaling pathway  branching involved in mammary gland duct morphogenesis  cellular response to interleukin-4  cellular senescence  negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process  regulation of double-strand break repair  positive regulation of extrinsic apoptotic signaling pathway  
    Pathways : BIOCARTARegulation of transcriptional activity by PML [Genes]   
    Pathways : KEGGUbiquitin mediated proteolysis    Endocytosis    Influenza A    Herpes simplex infection    Pathways in cancer    Transcriptional misregulation in cancer    Acute myeloid leukemia   
    REACTOMEPML
    Protein Interaction DatabasePML
    Wikipedia pathwaysPML
    Gene fusion - rearrangments
    Rearrangement : TICdbPAX5 [9p13.2]  -  PML [15q24.1]
    Rearrangement : TICdbPML [15q24.1]  -  PAX5 [9p13.2]
    Rearrangement : TICdbPML [15q24.1]  -  PML [15q24.1]
    Rearrangement : TICdbPML [15q24.1]  -  PML [15q24.1]
    Rearrangement : TICdbPML [15q24.1]  -  RARA [17q21.2]
    Rearrangement : TICdbRARA [17q21.2]  -  PML [15q24.1]
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)PML
    SNP (GeneSNP Utah)PML
    SNP : HGBasePML
    Genetic variants : HAPMAPPML
    1000_GenomesPML 
    ICGC programENSG00000140464 
    Cancer Gene: CensusPML 
    Somatic Mutations in Cancer : COSMICPML 
    CONAN: Copy Number AnalysisPML 
    Mutations and Diseases : HGMDPML
    OMIM102578   
    GENETestsPML
    Disease Genetic AssociationPML
    Huge Navigator PML [HugePedia]  PML [HugeCancerGEM]
    Genomic VariantsPML  PML [DGVbeta]
    Exome VariantPML
    dbVarPML
    ClinVarPML
    snp3D : Map Gene to Disease5371
    General knowledge
    Homologs : HomoloGenePML
    Homology/Alignments : Family Browser (UCSC)PML
    Phylogenetic Trees/Animal Genes : TreeFamPML
    Chemical/Protein Interactions : CTD5371
    Chemical/Pharm GKB GenePA33439
    Clinical trialPML
    Cancer Resource (Charite)ENSG00000140464
    Other databases
    Other databasePML at 15q22 in normal cells (Bari)
    Probes
    Litterature
    PubMed408 Pubmed reference(s) in Entrez
    CoreMinePML
    iHOPPML

    Bibliography

    The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.
    de Thˆ© H, Chomienne C, Lanotte M, Degos L, Dejean A
    Nature. 1990 ; 347 (6293) : 558-561.
    PMID 2170850
     
    Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.
    Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM
    Cell. 1991 ; 66 (4) : 663-674.
    PMID 1652368
     
    Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation.
    Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F, Avvisati G, Pelicci PG, Jetten AM
    Cancer research. 1992 ; 52 (13) : 3687-3692.
    PMID 1319828
     
    Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia.
    Chen Z, Tong JH, Dong S, Zhu J, Wang ZY, Chen SJ
    Genes, chromosomes & cancer. 1996 ; 15 (3) : 147-156.
    PMID 8721678
     
    Genetics of APL and the molecular basis of retinoic acid treatment.
    Casini T, Grignani F, Pelicci PG
    International journal of cancer. Journal international du cancer. 1997 ; 70 (4) : 473-474.
    PMID 9033658
     
    Structure, organization, and dynamics of promyelocytic leukemia protein nuclear bodies.
    Hodges M, Tissot C, Howe K, Grimwade D, Freemont PS
    American journal of human genetics. 1998 ; 63 (2) : 297-304.
    PMID 9683622
     
    The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease.
    Grimwade D
    British journal of haematology. 1999 ; 106 (3) : 591-613.
    PMID 10468848
     
    Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia.
    Melnick A, Licht JD
    Blood. 1999 ; 93 (10) : 3167-3215.
    PMID 10233871
     
    The transcriptional role of PML and the nuclear body.
    Zhong S, Salomoni P, Pandolfi PP
    Nature cell biology. 2000 ; 2 (5) : E85-E90.
    PMID 10806494
     
    REVIEW articlesautomatic search in PubMed
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    Contributor(s)

    Written10-2000Franck Viguié

    Citation

    This paper should be referenced as such :
    Viguié F . PML (Promyelocytic leukemia). Atlas Genet Cytogenet Oncol Haematol. October 2000 .
    URL : http://AtlasGeneticsOncology.org/Genes/PMLID41.html

    The various updated versions of this paper are referenced and archived by INIST as such :
    http://documents.irevues.inist.fr/bitstream/2042/37669/1/10-2000-PMLID41.pdf   [ Bibliographic record ]

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    indexed on : Fri Apr 18 17:42:10 CEST 2014

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