Disease relevance of PML

• A unique mRNA produced in leukemic cells from a t(15;17) acute promyelocytic leukemia (APL) patient encodes a fusion protein between the retinoic acid receptor alpha (RAR alpha) and a myeloid gene product called PML [1].
• Marrow mononuclear cells and reverse transcription-polymerase chain reaction (RT-PCR) analysis of messenger RNA encoded by the PML/RAR-alpha oncogene were used to assess minimal residual disease [2].
• Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARalpha-associated leukemias to ATRA [3].
• The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein [4].
• We demonstrate that PML acts as a coactivator for the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein without direct binding [5].

Psychiatry related information on PML

• Daxx accumulates in both the nucleus and the cytoplasm; in the nucleus, Daxx is found associated with the promyelocytic leukaemia (PML) nuclear body and with alpha-thalassemia/mental retardation syndrome protein (ATRX)-positive heterochromatic regions [6].
• BACKGROUND AND OBJECTIVES: The detection of PML-RAR by reverse transcription (RT) polymerase chain reaction (PCR) in acute promyelocytic leukemia (APL) patients who are in hematologic remission influences therapeutic decision making in several trials [7].
• RESULTS: Significantly higher levels of sCD23 were found in the CSF of the patients with brain lymphoma than in those with systemic NHL (P < 0.002) or with cerebral toxoplasmosis, PML and AIDS-related dementia (P < 0.0001) [8].
• A case of Wernicke's encephalopathy associated with promyelocytic leukemia found at autopsy is reported [9].

High impact information on PML

• Finally, deregulations in annexin expression and activity have been correlated with human diseases, e.g., in acute promyelocytic leukemia and the antiphospholipid antibody syndrome, and the term annexinopathies has been coined [10].
• Importantly, we found an inverse correlation between CK2 kinase activity and PML protein levels in human lung cancer-derived cell lines and primary specimens [11].
• The PML protein induces senescence, and, upon oncogenic stress, its absence promotes cellular transformation [12].
• Consequently, PML mutants that are resistant to CK2 phosphorylation display increased tumor-suppressive functions [11].
• The PML tumor suppressor controls key pathways for growth suppression, induction of apoptosis, and cellular senescence [11].

Chemical compound and disease context of PML

• The chromosomal translocation t(15;17)(q22:21) of acute promyelocytic leukemia (APL) fuses PML, a novel gene, with RAR alpha, a retinoic acid receptor gene [13].
• All-trans-retinoic acid (RA) treatment induces remissions in acute promyelocytic leukemia (APL) cases expressing the t(15;17) product, promyelocytic leukemia (PML)/RA receptor alpha (RARalpha) [14].
• PML residue lysine 160 is required for the degradation of PML induced by herpes simplex virus type 1 regulatory protein ICP0 [15].
• PML degradation was also observed in SK-BR3 breast cancer cells treated with RA [16].
• Androgen suppresses PML protein expression in prostate cancer CWR22R cells [17].

Biological context of PML

• Because patients with APL can be induced into remission with high dose RA therapy, we propose that the nonliganded PML-RAR protein is a new class of dominant negative oncogene product [1].
• Characterization of PML revealed that it is a putative zinc finger protein and potential transcription factor that is commonly expressed, with at least three major transcription products [18].
• PML appears to be involved in multiple functions, including apoptosis and transcriptional activation by RAR, whereas PML-RARalpha blocks these functions of PML [19].
• Finally, cAMP restored both RA-triggered differentiation and PML-RARA transcriptional activation in mutant RA-resistant APL cells [20].
• We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels [21].
• Targeting of the oligomerization of PML-RARalpha through coiled-coil-domain (PCC) peptides leads to an inhibition of the leukemic phenotype and is accompanied by protein degradation that efficiently destroys the oncogenicity of the fusion protein [22].

Anatomical context of PML

• Bone marrow mononuclear cells were serially monitored by flow cytometry for immunophenotype, fluorescence in situ hybridization, reverse-transcription-polymerase-chain-reaction (RT-PCR) assay for PML-RAR-alpha fusion transcripts, and Western blot analysis for expression of the apoptosis-associated proteins caspases 1, 2, and 3 [23].
• Treatment with RA would not only relieve this inhibition, but the activated PML-RAR protein may actually promote myelocyte differentiation [1].
• SuPr-1 action on transcription was enhanced by PML, and SuPr-1 failed to activate transcription in PML-deficient fibroblasts [24].
• Metabolic-energy-dependent movement of PML bodies within the mammalian cell nucleus [25].
• Introducing PML into this cell line by transient expression or fusion with PML-producing cells recruited ND10-associated proteins into de novo formed ND10 attesting to PMLs essential nature in ND10 formation [26].

Associations of PML with chemical compounds

• The aberrant PML-RAR fusion product, while typically retinoic acid responsive, displays both cell type- and promoter-specific differences from the wild-type RAR alpha [1].
• We show that both PML and Tif1alpha are growth suppressors required for the growth-inhibitory activity of RA [27].
• A hallmark of retinoid response in APL is the proteasome-dependent PML/RARalpha degradation [14].
• PML/RARalpha, a repressor of RA target genes, abolished this UBE1L promoter activity [14].
• The RA-induced differentiation of APL blasts is paralleled by the degradation of the fusion protein and the relocation of wild-type PML from aberrant nuclear structures to its normal localization in nuclear bodies [28].
• PML is involved in trichostatin A-induced apoptosis and PML with an acetylation-defective mutation shows an inability to mediate apoptosis, suggesting the importance of PML acetylation [29].

Physical interactions of PML

• Our findings suggest that BLM is part of a dynamic nuclear matrix-based complex that requires PML and functions during G2 in undamaged cells and recombinational repair after DNA damage [30].
• Here we exploit fluorescence resonance energy transfer (FRET) to demonstrate that cyclin T1 physically interacts in vivo with the promyelocytic leukaemia (PML) protein within specific subnuclear compartments that are coincident with PML nuclear bodies [31].
• In the majority (42 of 60), molecular analyses revealed underlying PML/RAR alpha rearrangements due to insertions (28 of 42) or more complex mechanisms, including 3-way and simple variant translocations (14 of 42) [32].
• The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor alpha in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation [33].
• PML colocalizes with and stabilizes the DNA damage response protein TopBP1 [34].

Co-localisations of PML

• We report that PML colocalizes with the nonphosphorylated fraction of the retinoblastoma protein (pRB) within nuclear bodies and that pRB is delocalized by PML-RAR alpha expression [4].
• N-terminal-truncated SENP5 co-localized with PML, a known SUMO substrate [35].
• It has also been shown to interact with and phosphorylate p53 and to form punctate speckles in the nucleus of which a proportion colocalize with PML nuclear bodies (ND10) [36].
• Double-staining and coimmunoprecipitation analyses suggested that RNF36 colocalizes and interacts with PML [37].
• Ankrd2 co-localizes with the transcriptional co-activator and co-repressor PML in nuclear bodies (NBs) in human myoblasts as detected by confocal immunofluorescence [38].

Regulatory relationships of PML

• PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2 [39].
• UBE1L transfection triggered PML/RARalpha degradation, but transfection of a truncated UBE1L or E1 did not cause this degradation [14].
• A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RAR alpha mutation [40].
• The present study demonstrates that PML represses transcription by functionally and physically interacting with histone deacetylase (HDAC) [41].
• Together, our findings demonstrate that PML regulates TopBP1 functions by association and stabilization of the protein in response to IR-induced DNA damage [34].
• In contrast to PML IV, the leukemia-associated PML-retinoic acid receptor alpha fusion protein dissociated the PU.1/PML IV/p300 complex and inhibited PU.1-induced transcription [42].

Other interactions of PML

• Identical PML-RAR alpha fusion points are found in several patients [43].
• Our findings identify the basic requirements for ND10 formation and suggest a dynamic mechanism for protein recruitment to these nuclear domains controlled by the SUMO-1 modification state of PML [26].
• In the absence of PML, Daxx is highly enriched in condensed chromatin [26].
• BLM localizes to promyelocytic leukemia protein (PML) nuclear bodies and is expressed during late S and G2 [30].
• Deletion mutants at the C-terminal region of cyclin T1 are negative for FRET with PML and fail to localize to nuclear bodies [31].
• Using this sensitive and quantitative SUMO BRET assay that distinguishes PML sumoylation from SBD-mediated PML/SUMO non-covalent interactions, we probed the respective roles of covalent and non-covalent PML/SUMO interactions in PML degradation and interaction with RNF4 [44].

Analytical, diagnostic and therapeutic context of PML

• Eight of 11 patients who initially tested positive for the PML-RAR-alpha fusion transcript by the RT-PCR assay later tested negative; 3 other patients, who persistently tested positive, relapsed early [23].
• Metaphase fluorescence in situ hybridization (FISH) demonstrated that insertions most commonly led to formation of the PML-RAR alpha fusion gene on 15q [32].
• The micropunctates characteristic of PML-RAR alpha in NB4 cells dissappear after treatment with As2O3, whereas a diffuse PML staining occurs in the perinuclear cytoplasmic region [45].
• No change was observed in the pattern of PML/RAR-alpha expression assessed by Northern blot analysis at the time of relapse compared with pretreatment in two patients who were tested [46].
• Coimmunoprecipitation and double-color immunofluorescence staining demonstrated that PML physically interacts with RelA/p65 in vivo and the two proteins colocalized at the endogenous levels [47].

References