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PML (promyelocytic leukemia)

Identity

Other namesMYL
RNF71
TRIM19
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]
 
  Top: Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Bottom: Metaphase FISH analysis of PML (green); red dots indicate centromere of chromosome 15 (Subramaniyam et al., 2006).

DNA/RNA

 
  Structural organization of PML human gene (Nisole et al., 2013).
Description PML is composed of 9 exons. Exons 7 and 8 can be divided into exons 7a, 7b, 8a and 8b.
Transcription Transcription of PML generates 22 transcripts (splice variants) with at least 11 different isoforms (PMLI, PMLIa, PMLII, PMLIIa, PMLIII, PMLIV, PMLIVa, PMLV, PMLVI, PMLVIIa, PMLVIIb). Names of PML isoforms are based on the original nomenclature defined by Jensen et al., 2001.
Pseudogene No pseudogenes have been reported so far.

Protein

 
  Schematic representation of PML isoforms (Nisole et al., 2013).
Description Alternative splicing of PML gives rise to several isoforms with different molecular weight: PMLI is the longest isoform and is composed of 882 amino acids, while the shortest is PMLVIIb (435 amino acids). PML belongs to the family of the tripartite motif (TRIM). The RBCC/TRIM motif is present in all PML isoforms and is encoded by the exons 1-3. The RBCC domain is composed of a RING finger domain (R), two B-boxes domains (B1 and B2) and an α-helical coiled-coil domain (CC). The RING finger motif is a conserved cysteine-rich zinc-binding domain found in several classes of proteins. The RING domain of PML is involved in the formation of the PML nuclear bodies (PML-NBs, see below) and in several others PML functions. Adjacent to the RING domain lay two cysteine-rich domains named B-boxes: these two domains have been proposed to work as second zinc-binding domain and they are involved in PML-NBs formation and in several others PML functions. The coiled-coil domain mediate PML homo- and hetero-dimerization. The CC domain is also essential for PML-NBs formation and PML functions. A nuclear localization signal (NLS) is present in the isoforms but not in PMLVIIb. The SUMO interacting motif (SIM) of PML is required for the recognition and binding of SUMOylated proteins (Jensen et al., 2001; Nisole et al., 2013). The SIM domain also contains the PML degron, involved in the CK2-dependent PML degradation (Scaglioni et al., 2006). PML undergoes several post-translational modifications. Several kinases phosphorylate PML on serine and threonine residues regulating its functions (Bernardi et al., 2004; Hayakawa and Privalsky, 2004; Scaglioni et al., 2006; Yang et al., 2006). SUMOylation is the most intensely studied post-translational modification of PML. Both SUMO1 and SUMO2/SUMO3 bind covalently to PML. SUMOylation facilitates PML-NBs formation promoting tumor suppressive response PML-dependent, but also promotes leukemogenesis by the SUMOylation of PML-RARA. Finally, SUMOylation also promotes ubiquitin-mediate degradation of PML and PML-RARA (Fu et al., 2005; Shen et al., 2006; Lallemand-Breitenbach et al., 2008; Kamitani et al., 1998a; Kamitani et al., 1998b; Rabellino et al., 2012). Ubiquitination regulates PML functions and activity and deregulation of PML appears to be the common mechanism accounting for PML loss in tumors (reviewed in Rabellino and Scaglioni, 2013). Finally, PML can be also acetylated (Hayakawa et al., 2008).
PML is the major constituent of the PML-NBs. PML-NBs are highly dynamic nuclear structures tightly bound to the nuclear matrix. Several functions of PML are related to the PML-NBs functions (reviewed in Bernardi et al., 2007). More than 150 different proteins have been shown to localize into PML-NBs (Van Damme et al., 2010).
 
  Schematic representation of PML isoform IV protein domains. R = RING-finger domains, aa 55-91; B1, B2 = B-boxes 1 aa 124-166 and 2 aa 184-228; CC = α-helical coiled-coil domain, aa 233-360; N = nuclear localization signal, aa 428-442; SIM = SUMO interacting motif, 508-518; D = degron. The three major SUMOylation sites (K60, K160 and K442) are indicated, as well as the major phosphorylation sites (T28, S36, S40, S480, T482, S517).
Expression PML is ubiquitously expressed.
 
Localisation Nuclear (PMLI-VI) and cytoplasmic (PMLVIIb).
Function PML has been implicated in several cellular functions.
Cellular senescence: PML is a key regulator of cellular senescence. PML is involved in oncogenic-induced senescence (OIS) K-RAS dependent in a p53 dependent way (de Stanchina et al., 2004; Ferbeyre et al., 2000; Pearson et al., 2000; Scaglioni et al., 2012). PML is also involved in Rb-dependent senescence (Mallette et al., 2004).
Apoptosis: PML promotes apoptosis primarily by its ability to interact with p53 (Wang et al., 1998). Moreover, a pro-apoptotic function has been also attributed to the cytoplasmic isoform of PML (Giorgi et al., 2010).
Neoangiogenesis: PML represses HIF1 transcription, blocking de novo angiogenesis (Bernardi et al., 2006).
Cell migration: PML is involved in the regulation of cell migration by the negatively regulating of β-1 integrins (Reineke et al., 2010).
DNA damage response: several proteins involved in DNA repair have been report to reside into PML-NBs. Therefore, PML is also involved in DNA-repair, even though the mechanisms are still not completely clear (reviewed in Dellaire and Bazett-Jones, 2004).
Anti-viral response: several viral proteins interact with PML and the PML-NBs; moreover, several reports implicate PML and PML-NBs in anti-viral response (reviewed in Geoffroy and Chelbi-Alix, 2011).
Hematopoietic stem cell maintenance: PML has been reported being involved in hematopoietic stem cell maintenance by the regulation of the fatty acid oxidation (Ito et al., 2008; Ito et al., 2012).
Several functions of PML are related to its ability to form PML-NBs. PML-NBs have been involved in tumor suppression, senescence and apoptosis, DNA-damage response, cell migration, neoangiogenesis and anti-viral response (reviewed in Bernardi et al., 2007).
Homology PML is conserved in Amniota (source: HomoloGene).

Mutations

Note PML-RARA is the product of the chromosomal translocation t(15;17) and it causes acute promyelocytic leukemia (APL) (de Thé et al., 1990; Goddard et al., 1991; Kakizuka et al., 1991; Pandolfi et al., 1991).
 
  Schematic representation of the mutations type of human PML found in human tumor samples (source COSMIC).
Germinal No germinal mutations of PML have been reported.
Somatic At least 65 different somatic mutations have been described. All the informations in this regard can be found at the COSMIC website.

Implicated in

Entity Acute promyelocytic leukemia (APL)
Note (de Thé et al., 1990; Goddard et al., 1991; Kakizuka et al., 1991; Pandolfi et al., 1991)
Disease The balanced chromosomal translocation t(15;17)(q24;q21) causes APL by driving the synthesis of the PML-RARA oncoprotein. This translocation drives the production of three different PML-RARA variants, depending on the length of the PML module: a short variant PML(S)-RARA, an intermediate variant PML(V)-RARA and a long variant PML(L)-RARA. Generally, 70% of the APL patients carry the PML(L)-RARA variant, followed by the PML(S)-RARA variant (20%) and the PML(V)-RARA (10%) (Melnick and Licht, 1999). PML staining in APL cells show a characteristic pattern commonly named "microspeckles" due to the fact that PML-RARA disrupts the PML-NBs. PML-RARA acts as a transcriptional repressor of RARA target genes. At the same time PML-RARA physically interacts with PML, impairing its tumor-suppressive functions. Combined, these features lead to the aberrant self-renewal of hematopoietic stem cells and block of differentiation of myeloid precursor cells at the promyelocytic stage (de Thé et al., 2012). APL is a distinct subtype of acute myeloid leukemia (AML), is a rare condition though extremely aggressive and malignant. Clinically, APL symptoms tend to be similar to AML. APL is characterized by a severe coagulopathy, including disseminated intravascular coagulation (DIC).
Prognosis APL is normally treated with the combination of retinoic acid (ATRA) and arsenic trioxide (ATO). This therapy leads to the remission of the disease in more than 90% of the cases. Notably, APL was the first malignant disease cured with targeted therapy (Lo-Coco et al., 2013).
  
Entity B-cell acute lymphoblastic leukemia (B-ALL)
Note (Nebral et al., 2007; Qiu et al., 2011; Kurahashi et al., 2011)
Disease The transcription factor PAX5 is required for development and maintenance of B-cell. Several chromosomal translocations involving PAX5 have been described, including the t(9;15)(p13;q24) in which the 5' region of PAX5 is fused to PML. So far, two cases of B-ALL PAX5-PML-dependent have been reported. The fused PAX5-PML oncoprotein has a dominant-negative effect on both PML and PAX5, inhibiting PAX5 activation of B-cell specific genes and disrupting PML-NBs formation.
Prognosis Kurahashi and colleagues suggest that B-ALL PAX5-PML dependent could be treated with ATO (Kurahashi et al., 2011).
  
Entity Various cancers
Note Several reports indicate a reduced PML expression in several cancer types (Gurrieri et al., 2004; Rabellino et al., 2012; Rabellino and Scaglioni, 2013).
Disease PML protein expression was reduced or abolished in prostate adenocarcinomas (63% [95% confidence interval {CI} = 48% to 78%] and 28% [95% CI = 13% to 43%], respectively), colon adenocarcinomas (31% [95% CI = 22% to 40%] and 17% [95% CI = 10% to 24%]), breast carcinomas (21% [95% CI = 8% to 34%] and 31% [95% CI = 16% to 46%]), lung carcinomas (36% [95% CI = 15% to 57%] and 21% [95% = 3% to 39%]), lymphomas (14% [95% CI = 10% to 18%] and 69% [95% CI = 63% to 75%]), CNS tumors (24% [95% CI = 13% to 35%] and 49% [95% CI = 36% to 62%]), and germ cell tumors (36% [95% CI = 24% to 48%] and 48% [95% CI = 36% to 60%]) but not in thyroid or adrenal carcinomas (Gurrieri et al., 2004). In all the cases, PML mRNA levels are comparable to the healthy tissues and the PML gene is rarely mutated, but the protein levels of PML are reduced. This correlates with several reports that underline the role of PML degradation in tumor progression and maintenance (reviewed in Rabellino and Scaglioni, 2013).
Prognosis In most of the cases, loss of PML is associated with tumor progression, like was reported for prostate cancer, breast cancer and CNS tumors (Gurrieri et al., 2004).
  

Breakpoints

 
 
Note Breakpoint at q24, responsible of translocation t(15;17)(q24;q21).

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615 11q23ID1030 11q23secondLeukID1131 t1119ELLID1029 t0812q24q22ID2057

External links

Nomenclature
HGNC (Hugo)PML   9113
Cards
AtlasPMLID41
Entrez_Gene (NCBI)PML  5371  promyelocytic leukemia
GeneCards (Weizmann)PML
Ensembl hg19 (Hinxton)ENSG00000140464 [Gene_View]  chr15:74287014-74335717 [Contig_View]  PML [Vega]
Ensembl hg38 (Hinxton)ENSG00000140464 [Gene_View]  chr15:74287014-74335717 [Contig_View]  PML [Vega]
ICGC DataPortalENSG00000140464
cBioPortalPML
AceView (NCBI)PML
Genatlas (Paris)PML
WikiGenes5371
SOURCE (Princeton)PML
Genomic and cartography
GoldenPath hg19 (UCSC)PML  -     chr15:74287014-74335717 +  15q24.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PML  -     15q24.1   [Description]    (hg38-Dec_2013)
EnsemblPML - 15q24.1 [CytoView hg19]  PML - 15q24.1 [CytoView hg38]
Mapping of homologs : NCBIPML [Mapview hg19]  PML [Mapview hg38]
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 ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
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
IntegromeDBPML
STRING (EMBL)PML
Ontologies - Pathways
QuickGOP29590
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-templated  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  intrinsic apoptotic signaling pathway in response to oxidative stress  response to UV  response to gamma radiation  regulation of calcium ion transport into cytosol  viral process  nuclear matrix  nuclear matrix  negative regulation of angiogenesis  PML body  PML body  PML body  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  circadian regulation of gene expression  negative regulation of translation in response to oxidative stress  response to cytokine  extrinsic component of endoplasmic reticulum membrane  regulation of circadian rhythm  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  protein homodimerization activity  entrainment of circadian clock by photoperiod  proteasome-mediated ubiquitin-dependent protein catabolic process  innate immune response  cell fate commitment  regulation of MHC class I biosynthetic process  negative regulation of transcription, DNA-templated  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  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  cellular response to interleukin-4  cellular senescence  extrinsic apoptotic signaling pathway  negative regulation of viral release from host cell  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-templated  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  intrinsic apoptotic signaling pathway in response to oxidative stress  response to UV  response to gamma radiation  regulation of calcium ion transport into cytosol  viral process  nuclear matrix  nuclear matrix  negative regulation of angiogenesis  PML body  PML body  PML body  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  circadian regulation of gene expression  negative regulation of translation in response to oxidative stress  response to cytokine  extrinsic component of endoplasmic reticulum membrane  regulation of circadian rhythm  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  protein homodimerization activity  entrainment of circadian clock by photoperiod  proteasome-mediated ubiquitin-dependent protein catabolic process  innate immune response  cell fate commitment  regulation of MHC class I biosynthetic process  negative regulation of transcription, DNA-templated  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  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  cellular response to interleukin-4  cellular senescence  extrinsic apoptotic signaling pathway  negative regulation of viral release from host cell  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   
REACTOMEP29590 [protein]
REACTOME PathwaysREACT_6900 Immune System [pathway]
Protein Interaction DatabasePML
DoCM (Curated mutations)PML
Wikipedia pathwaysPML
Gene fusion - rearrangements
Rearrangement : TICdbPML [15q24.1]  -  RARA [8q21.3]
Rearrangement : TICdbPAX5 [9p13.2]  -  PML [5q32]
Polymorphisms : SNP, variants
NCBI Variation ViewerPML [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PML
dbVarPML
ClinVarPML
1000_GenomesPML 
Exome Variant ServerPML
SNP (GeneSNP Utah)PML
SNP : HGBasePML
Genetic variants : HAPMAPPML
Genomic VariantsPML  PML [DGVbeta]
Mutations
ICGC Data PortalENSG00000140464 
Cancer Gene: CensusPML 
Somatic Mutations in Cancer : COSMICPML 
CONAN: Copy Number AnalysisPML 
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
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)15:74287014-74335717
Mutations and Diseases : HGMDPML
OMIM102578   
MedgenPML
NextProtP29590 [Medical]
GENETestsPML
Disease Genetic AssociationPML
Huge Navigator PML [HugePedia]  PML [HugeCancerGEM]
snp3D : Map Gene to Disease5371
DGIdb (Drug Gene Interaction db)PML
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
Probes
Litterature
PubMed425 Pubmed reference(s) in Entrez
CoreMinePML
GoPubMedPML
iHOPPML

Bibliography

The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.
de The H, Chomienne C, Lanotte M, Degos L, Dejean A.
Nature. 1990 Oct 11;347(6293):558-61.
PMID 2170850
 
Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia.
Goddard AD, Borrow J, Freemont PS, Solomon E.
Science. 1991 Nov 29;254(5036):1371-4.
PMID 1720570
 
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 Aug 23;66(4):663-74.
PMID 1652368
 
Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties.
Pandolfi PP, Grignani F, Alcalay M, Mencarelli A, Biondi A, LoCoco F, Grignani F, Pelicci PG.
Oncogene. 1991 Jul;6(7):1285-92.
PMID 1650447
 
Identification of three major sentrinization sites in PML.
Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani T, Yeh ET.
J Biol Chem. 1998a Oct 9;273(41):26675-82.
PMID 9756909
 
Covalent modification of PML by the sentrin family of ubiquitin-like proteins.
Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ET.
J Biol Chem. 1998b Feb 6;273(6):3117-20.
PMID 9452416
 
PML is essential for multiple apoptotic pathways.
Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R, Pandolfi PP.
Nat Genet. 1998 Nov;20(3):266-72.
PMID 9806545
 
Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia.
Melnick A, Licht JD.
Blood. 1999 May 15;93(10):3167-215. (REVIEW)
PMID 10233871
 
PML is induced by oncogenic ras and promotes premature senescence.
Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW.
Genes Dev. 2000 Aug 15;14(16):2015-27.
PMID 10950866
 
PML regulates p53 acetylation and premature senescence induced by oncogenic Ras.
Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP, Pelicci PG.
Nature. 2000 Jul 13;406(6792):207-10.
PMID 10910364
 
PML protein isoforms and the RBCC/TRIM motif.
Jensen K, Shiels C, Freemont PS.
Oncogene. 2001 Oct 29;20(49):7223-33. (REVIEW)
PMID 11704850
 
PML regulates p53 stability by sequestering Mdm2 to the nucleolus.
Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP.
Nat Cell Biol. 2004 Jul;6(7):665-72. Epub 2004 Jun 13.
PMID 15195100
 
PML is a direct p53 target that modulates p53 effector functions.
de Stanchina E, Querido E, Narita M, Davuluri RV, Pandolfi PP, Ferbeyre G, Lowe SW.
Mol Cell. 2004 Feb 27;13(4):523-35.
PMID 14992722
 
PML nuclear bodies: dynamic sensors of DNA damage and cellular stress.
Dellaire G, Bazett-Jones DP.
Bioessays. 2004 Sep;26(9):963-77. (REVIEW)
PMID 15351967
 
Loss of the tumor suppressor PML in human cancers of multiple histologic origins.
Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ, Verbel DA, Cordon-Cardo C, Pandolfi PP.
J Natl Cancer Inst. 2004 Feb 18;96(4):269-79.
PMID 14970276
 
Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis.
Hayakawa F, Privalsky ML.
Cancer Cell. 2004 Apr;5(4):389-401.
PMID 15093545
 
Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence.
Mallette FA, Goumard S, Gaumont-Leclerc MF, Moiseeva O, Ferbeyre G.
Oncogene. 2004 Jan 8;23(1):91-9.
PMID 14712214
 
Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3.
Fu C, Ahmed K, Ding H, Ding X, Lan J, Yang Z, Miao Y, Zhu Y, Shi Y, Zhu J, Huang H, Yao X.
Oncogene. 2005 Aug 18;24(35):5401-13.
PMID 15940266
 
PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR.
Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP.
Nature. 2006 Aug 17;442(7104):779-85.
PMID 16915281
 
A CK2-dependent mechanism for degradation of the PML tumor suppressor.
Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B, Teruya-Feldstein J, Tempst P, Pandolfi PP.
Cell. 2006 Jul 28;126(2):269-83.
PMID 16873060
 
The mechanisms of PML-nuclear body formation.
Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP.
Mol Cell. 2006 Nov 3;24(3):331-9.
PMID 17081985
 
Do RARA/PML fusion gene deletions confer resistance to ATRA-based therapy in patients with acute promyelocytic leukemia?
Subramaniyam S, Nandula SV, Nichols G, Weiner M, Satwani P, Alobeid B, Bhagat G, Murty VV.
Leukemia. 2006 Dec;20(12):2193-5. Epub 2006 Sep 28.
PMID 17008891
 
Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation.
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Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies.
Bernardi R, Pandolfi PP.
Nat Rev Mol Cell Biol. 2007 Dec;8(12):1006-16. (REVIEW)
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Identification of PML as novel PAX5 fusion partner in childhood acute lymphoblastic leukaemia.
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Br J Haematol. 2007 Oct;139(2):269-74.
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Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis.
Hayakawa F, Abe A, Kitabayashi I, Pandolfi PP, Naoe T.
J Biol Chem. 2008 Sep 5;283(36):24420-5. doi: 10.1074/jbc.M802217200. Epub 2008 Jul 11.
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PML targeting eradicates quiescent leukaemia-initiating cells.
Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi PP.
Nature. 2008 Jun 19;453(7198):1072-8. doi: 10.1038/nature07016. Epub 2008 May 11.
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Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway.
Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de The H.
Nat Cell Biol. 2008 May;10(5):547-55. doi: 10.1038/ncb1717. Epub 2008 Apr 13.
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PML regulates apoptosis at endoplasmic reticulum by modulating calcium release.
Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP.
Science. 2010 Nov 26;330(6008):1247-51. doi: 10.1126/science.1189157. Epub 2010 Oct 28.
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Promyelocytic leukemia protein controls cell migration in response to hydrogen peroxide and insulin-like growth factor-1.
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J Biol Chem. 2010 Mar 26;285(13):9485-92. doi: 10.1074/jbc.M109.063362. Epub 2010 Jan 25.
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A manually curated network of the PML nuclear body interactome reveals an important role for PML-NBs in SUMOylation dynamics.
Van Damme E, Laukens K, Dang TH, Van Ostade X.
Int J Biol Sci. 2010 Jan 12;6(1):51-67. (REVIEW)
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J Interferon Cytokine Res. 2011 Jan;31(1):145-58. doi: 10.1089/jir.2010.0111. Epub 2011 Jan 3. (REVIEW)
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PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML.
Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, Abe A, Naoe T.
Oncogene. 2011 Apr 14;30(15):1822-30. doi: 10.1038/onc.2010.554. Epub 2011 Jan 10.
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The reduced and altered activities of PAX5 are linked to the protein-protein interaction motif (coiled-coil domain) of the PAX5-PML fusion protein in t(9;15)-associated acute lymphocytic leukemia.
Qiu JJ, Chu H, Lu X, Jiang X, Dong S.
Oncogene. 2011 Feb 24;30(8):967-77. doi: 10.1038/onc.2010.473. Epub 2010 Oct 25.
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The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.
de The H, Le Bras M, Lallemand-Breitenbach V.
J Cell Biol. 2012 Jul 9;198(1):11-21. doi: 10.1083/jcb.201112044. (REVIEW)
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A PML-PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance.
Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, Schafer ZT, Evans RM, Suda T, Lee CH, Pandolfi PP.
Nat Med. 2012 Sep;18(9):1350-8.
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The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA.
Rabellino A, Carter B, Konstantinidou G, Wu SY, Rimessi A, Byers LA, Heymach JV, Girard L, Chiang CM, Teruya-Feldstein J, Scaglioni PP.
Cancer Res. 2012 May 1;72(9):2275-84. doi: 10.1158/0008-5472.CAN-11-3159. Epub 2012 Mar 9.
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Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence.
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Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lubbert M, Hanel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Dohner K, Sauer M, Ganser A, Amadori S, Mandelli F, Dohner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia.
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Differential Roles of PML Isoforms.
Nisole S, Maroui MA, Mascle XH, Aubry M, Chelbi-Alix MK.
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PML Degradation: Multiple Ways to Eliminate PML.
Rabellino A, Scaglioni PP.
Front Oncol. 2013 Mar 22;3:60. doi: 10.3389/fonc.2013.00060. eCollection 2013.
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Contributor(s)

Written10-2000Franck Viguié
Laboratoire de Cytogenetique - Service d'Hematologie Biologique, Hopital Hotel-Dieu, 75181 Paris Cedex 04, France
Updated05-2014Andrea Rabellino, Pier Paolo Scaglioni
Division of Hematology and Oncology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

Citation

This paper should be referenced as such :
Rabellino A, Scaglioni PP
PML (promyelocytic leukemia);
Atlas Genet Cytogenet Oncol Haematol. May 2014
Free online version   Free pdf version   [Bibliographic record ]
Atlas Genet Cytogenet Oncol Haematol. May 2014
URL : http://AtlasGeneticsOncology.org/Genes/PMLID41.html

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