PML (promyelocytic leukemia)

2014-05-01   Andrea Rabellino , Pier Paolo Scaglioni 

Division of Hematology, Oncology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

Identity

HGNC
LOCATION
15q24.1
IMAGE
Atlas Image
LEGEND
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).
LOCUSID
ALIAS
MYL,PP8675,RNF71,TRIM19
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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).
Atlas Image
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).
Atlas Image
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

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 name
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 name
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

Atlas Image

Note

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

Bibliography

Pubmed IDLast YearTitleAuthors
179288112007Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies.Bernardi R et al
153519672004PML nuclear bodies: dynamic sensors of DNA damage and cellular stress.Dellaire G et al
109508662000PML is induced by oncogenic ras and promotes premature senescence.Ferbeyre G et al
159402662005Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3.Fu C et al
211983512011Role of promyelocytic leukemia protein in host antiviral defense.Geoffroy MC et al
210306052010PML regulates apoptosis at endoplasmic reticulum by modulating calcium release.Giorgi C et al
17205701991Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia.Goddard AD et al
149702762004Loss of the tumor suppressor PML in human cancers of multiple histologic origins.Gurrieri C et al
186217392008Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis.Hayakawa F et al
184698012008PML targeting eradicates quiescent leukaemia-initiating cells.Ito K et al
229028762012A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance.Ito K et al
117048502001PML protein isoforms and the RBCC/TRIM motif.Jensen K et al
16523681991Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.Kakizuka A et al
94524161998Covalent modification of PML by the sentrin family of ubiquitin-like proteins.Kamitani T et al
212177752011PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML.Kurahashi S et al
184087332008Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway.Lallemand-Breitenbach V et al
238417292013Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.Lo-Coco F et al
147122142004Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence.Mallette FA et al
102338711999Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia.Melnick A et al
178973022007Identification of PML as novel PAX5 fusion partner in childhood acute lymphoblastic leukaemia.Nebral K et al
237343432013Differential Roles of PML Isoforms.Nisole S et al
16504471991Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties.Pandolfi PP et al
109103642000PML regulates p53 acetylation and premature senescence induced by oncogenic Ras.Pearson M et al
209724552011The 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 et al
235267632013PML Degradation: Multiple Ways to Eliminate PML.Rabellino A et al
201008382010Promyelocytic leukemia protein controls cell migration in response to hydrogen peroxide and insulin-like growth factor-1.Reineke EL et al
223593422012Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence.Scaglioni PP et al
170819852006The mechanisms of PML-nuclear body formation.Shen TH et al
170088912006Do RARA/PML fusion gene deletions confer resistance to ATRA-based therapy in patients with acute promyelocytic leukemia?Subramaniyam S et al
200874422010A manually curated network of the PML nuclear body interactome reveals an important role for PML-NBs in SUMOylation dynamics.Van Damme E et al
98065451998PML is essential for multiple apoptotic pathways.Wang ZG et al
168352272006Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation.Yang S et al
149927222004PML is a direct p53 target that modulates p53 effector functions.de Stanchina E et al
21708501990The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.de Thé H et al
227782762012The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.de Thé H et al

Other Information

Locus ID:

NCBI: 5371
MIM: 102578
HGNC: 9113
Ensembl: ENSG00000140464

Variants:

dbSNP: 5371
ClinVar: 5371
TCGA: ENSG00000140464
COSMIC: PML

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000140464ENST00000268058P29590
ENSG00000140464ENST00000268059P29590
ENSG00000140464ENST00000354026P29590
ENSG00000140464ENST00000359928P29590
ENSG00000140464ENST00000395132P29590
ENSG00000140464ENST00000395135P29590
ENSG00000140464ENST00000435786P29590
ENSG00000140464ENST00000436891P29590
ENSG00000140464ENST00000562086H3BRN3
ENSG00000140464ENST00000563500H3BT57
ENSG00000140464ENST00000564428P29590
ENSG00000140464ENST00000565239H3BT29
ENSG00000140464ENST00000565898P29590
ENSG00000140464ENST00000566068H3BVD2
ENSG00000140464ENST00000567543P29590
ENSG00000140464ENST00000567606H3BUJ5
ENSG00000140464ENST00000569477P29590
ENSG00000140464ENST00000569965P29590

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Acute myeloid leukemiaKEGGko05221
Ubiquitin mediated proteolysisKEGGhsa04120
Pathways in cancerKEGGhsa05200
Acute myeloid leukemiaKEGGhsa05221
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of DNA damage response and repair proteinsREACTOMER-HSA-3108214
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Interferon SignalingREACTOMER-HSA-913531
Interferon gamma signalingREACTOMER-HSA-877300
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through AcetylationREACTOMER-HSA-6804758

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA448486arsenic trioxideChemicalLabelAnnotation, Literature, MultilinkAnnotationassociated24433361
PA451746tretinoinChemicalLabelAnnotationassociated

References

Pubmed IDYearTitleCitations
120064912002Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence.265
187166202008The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network.198
168732562006PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0.192
168732572006Evidence for a role of the cellular ND10 protein PML in mediating intrinsic immunity against human cytomegalovirus infections.132
149927222004PML is a direct p53 target that modulates p53 effector functions.121
149702762004Loss of the tumor suppressor PML in human cancers of multiple histologic origins.111
190299802008Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation.106
201596092010PML-RARalpha/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia.104
211983512011Role of promyelocytic leukemia protein in host antiviral defense.102
171730412007Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus.100

Citation

Andrea Rabellino ; Pier Paolo Scaglioni

PML (promyelocytic leukemia)

Atlas Genet Cytogenet Oncol Haematol. 2014-05-01

Online version: http://atlasgeneticsoncology.org/gene/41/pml-(promyelocytic-leukemia)

Historical Card

2000-10-01 PML (promyelocytic leukemia) by  Franck Viguié 

Laboratoire de Cytogenetique - Service dHematologie Biologique, Hopital Hotel-Dieu - 75181 Paris Cedex 04, France