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Gene Review

PML  -  promyelocytic leukemia

Homo sapiens

Synonyms: MYL, PP8675, RNF71, TRIM19
 
 
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Disease relevance of PML

 

Psychiatry related information on PML

 

High impact information on PML

 

Chemical compound and disease context of PML

 

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

 

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

  1. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Kakizuka, A., Miller, W.H., Umesono, K., Warrell, R.P., Frankel, S.R., Murty, V.V., Dmitrovsky, E., Evans, R.M. Cell (1991) [Pubmed]
  2. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. Warrell, R.P., He, L.Z., Richon, V., Calleja, E., Pandolfi, P.P. J. Natl. Cancer Inst. (1998) [Pubmed]
  3. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Guidez, F., Ivins, S., Zhu, J., Söderström, M., Waxman, S., Zelent, A. Blood (1998) [Pubmed]
  4. The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein. Alcalay, M., Tomassoni, L., Colombo, E., Stoldt, S., Grignani, F., Fagioli, M., Szekely, L., Helin, K., Pelicci, P.G. Mol. Cell. Biol. (1998) [Pubmed]
  5. Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein. Ariumi, Y., Ego, T., Kaida, A., Matsumoto, M., Pandolfi, P.P., Shimotohno, K. Oncogene (2003) [Pubmed]
  6. Daxx: death or survival protein? Salomoni, P., Khelifi, A.F. Trends Cell Biol. (2006) [Pubmed]
  7. Variability in the levels of PML-RAR alpha fusion transcripts detected by the laboratories participating in an external quality control program using several reverse transcription polymerase chain reaction protocols. Bolufer, P., Lo Coco, F., Grimwade, D., Barragán, E., Diverio, D., Cassinat, B., Chomienne, C., Gonzalez, M., Colomer, D., Gomez, M.T., Marugan, I., Román, J., Delgado, M.D., García-Marco, J.A., Bornstein, R., Vizmanos, J.L., Martinez, B., Jansen, J., Villegas, A., de Blas, J.M., Cabello, P., Sanz, M.A. Haematologica (2001) [Pubmed]
  8. Soluble CD23 in cerebrospinal fluid: a marker of AIDS-related non-Hodgkin's lymphoma in the brain. Bossolasco, S., Nilsson, A., de Milito, A., Lazzarin, A., Linde, A., Cinque, P., Chiodi, F. AIDS (2001) [Pubmed]
  9. Wernicke's encephalopathy manifested as Korsakoff's syndrome in a patient with promyelocytic leukemia. Pittella, J.E., de Castro, L.P. South. Med. J. (1990) [Pubmed]
  10. Annexins: from structure to function. Gerke, V., Moss, S.E. Physiol. Rev. (2002) [Pubmed]
  11. A CK2-dependent mechanism for degradation of the PML tumor suppressor. Scaglioni, P.P., Yung, T.M., Cai, L.F., Erdjument-Bromage, H., Kaufman, A.J., Singh, B., Teruya-Feldstein, J., Tempst, P., Pandolfi, P.P. Cell (2006) [Pubmed]
  12. CK2 and PML: regulating the regulator. Lallemand-Breitenbach, V., de Thé, H. Cell (2006) [Pubmed]
  13. Correlation of CD2 expression with PML gene breakpoints in patients with acute promyelocytic leukemia. Claxton, D.F., Reading, C.L., Nagarajan, L., Tsujimoto, Y., Andersson, B.S., Estey, E., Cork, A., Huh, Y.O., Trujillo, J., Deisseroth, A.B. Blood (1992) [Pubmed]
  14. UBE1L is a retinoid target that triggers PML/RARalpha degradation and apoptosis in acute promyelocytic leukemia. Kitareewan, S., Pitha-Rowe, I., Sekula, D., Lowrey, C.H., Nemeth, M.J., Golub, T.R., Freemantle, S.J., Dmitrovsky, E. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  15. PML residue lysine 160 is required for the degradation of PML induced by herpes simplex virus type 1 regulatory protein ICP0. Boutell, C., Orr, A., Everett, R.D. J. Virol. (2003) [Pubmed]
  16. Promyelocytic leukemia protein-induced growth suppression and cell death in liver cancer cells. Son, S.H., Yu, E., Choi, E.K., Lee, H., Choi, J. Cancer Gene Ther. (2005) [Pubmed]
  17. Androgen suppresses PML protein expression in prostate cancer CWR22R cells. Yang, L., Yeh, S.D., Xie, S., Altuwaijri, S., Ni, J., Hu, Y.C., Chen, Y.T., Bao, B.Y., Su, C.H., Chang, C. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  18. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Goddard, A.D., Borrow, J., Freemont, P.S., Solomon, E. Science (1991) [Pubmed]
  19. Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Khan, M.M., Nomura, T., Kim, H., Kaul, S.C., Wadhwa, R., Shinagawa, T., Ichikawa-Iwata, E., Zhong, S., Pandolfi, P.P., Ishii, S. Mol. Cell (2001) [Pubmed]
  20. PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. Kamashev, D., Vitoux, D., De Thé, H. J. Exp. Med. (2004) [Pubmed]
  21. Ubiquitin-dependent degradation of p73 is inhibited by PML. Bernassola, F., Salomoni, P., Oberst, A., Di Como, C.J., Pagano, M., Melino, G., Pandolfi, P.P. J. Exp. Med. (2004) [Pubmed]
  22. Targeting the Acute Promyelocytic Leukemia-Associated Fusion Proteins PML/RARα and PLZF/RARα with Interfering Peptides. Beez, S., Demmer, P., Puccetti, E. PLoS. One. (2012) [Pubmed]
  23. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. Soignet, S.L., Maslak, P., Wang, Z.G., Jhanwar, S., Calleja, E., Dardashti, L.J., Corso, D., DeBlasio, A., Gabrilove, J., Scheinberg, D.A., Pandolfi, P.P., Warrell, R.P. N. Engl. J. Med. (1998) [Pubmed]
  24. SUMO-1 protease-1 regulates gene transcription through PML. Best, J.L., Ganiatsas, S., Agarwal, S., Changou, A., Salomoni, P., Shirihai, O., Meluh, P.B., Pandolfi, P.P., Zon, L.I. Mol. Cell (2002) [Pubmed]
  25. Metabolic-energy-dependent movement of PML bodies within the mammalian cell nucleus. Muratani, M., Gerlich, D., Janicki, S.M., Gebhard, M., Eils, R., Spector, D.L. Nat. Cell Biol. (2002) [Pubmed]
  26. PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. Ishov, A.M., Sotnikov, A.G., Negorev, D., Vladimirova, O.V., Neff, N., Kamitani, T., Yeh, E.T., Strauss, J.F., Maul, G.G. J. Cell Biol. (1999) [Pubmed]
  27. A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18 oncoproteins. Zhong, S., Delva, L., Rachez, C., Cenciarelli, C., Gandini, D., Zhang, H., Kalantry, S., Freedman, L.P., Pandolfi, P.P. Nat. Genet. (1999) [Pubmed]
  28. Trivalent antimonials induce degradation of the PML-RAR oncoprotein and reorganization of the promyelocytic leukemia nuclear bodies in acute promyelocytic leukemia NB4 cells. Müller, S., Miller, W.H., Dejean, A. Blood (1998) [Pubmed]
  29. Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis. Hayakawa, F., Abe, A., Kitabayashi, I., Pandolfi, P.P., Naoe, T. J. Biol. Chem. (2008) [Pubmed]
  30. Regulation and localization of the Bloom syndrome protein in response to DNA damage. Bischof, O., Kim, S.H., Irving, J., Beresten, S., Ellis, N.A., Campisi, J. J. Cell Biol. (2001) [Pubmed]
  31. Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein. Marcello, A., Ferrari, A., Pellegrini, V., Pegoraro, G., Lusic, M., Beltram, F., Giacca, M. EMBO J. (2003) [Pubmed]
  32. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Grimwade, D., Biondi, A., Mozziconacci, M.J., Hagemeijer, A., Berger, R., Neat, M., Howe, K., Dastugue, N., Jansen, J., Radford-Weiss, I., Lo Coco, F., Lessard, M., Hernandez, J.M., Delabesse, E., Head, D., Liso, V., Sainty, D., Flandrin, G., Solomon, E., Birg, F., Lafage-Pochitaloff, M. Blood (2000) [Pubmed]
  33. The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. Melnick, A.M., Westendorf, J.J., Polinger, A., Carlile, G.W., Arai, S., Ball, H.J., Lutterbach, B., Hiebert, S.W., Licht, J.D. Mol. Cell. Biol. (2000) [Pubmed]
  34. PML colocalizes with and stabilizes the DNA damage response protein TopBP1. Xu, Z.X., Timanova-Atanasova, A., Zhao, R.X., Chang, K.S. Mol. Cell. Biol. (2003) [Pubmed]
  35. Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. Gong, L., Yeh, E.T. J. Biol. Chem. (2006) [Pubmed]
  36. The homeodomain-interacting kinase PKM (HIPK-2) modifies ND10 through both its kinase domain and a SUMO-1 interaction motif and alters the posttranslational modification of PML. Engelhardt, O.G., Boutell, C., Orr, A., Ullrich, E., Haller, O., Everett, R.D. Exp. Cell Res. (2003) [Pubmed]
  37. Forced expression of RNF36 induces cell apoptosis. Shyu, H.W., Hsu, S.H., Hsieh-Li, H.M., Li, H. Exp. Cell Res. (2003) [Pubmed]
  38. The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle. Kojic, S., Medeot, E., Guccione, E., Krmac, H., Zara, I., Martinelli, V., Valle, G., Faulkner, G. J. Mol. Biol. (2004) [Pubmed]
  39. PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Yang, S., Kuo, C., Bisi, J.E., Kim, M.K. Nat. Cell Biol. (2002) [Pubmed]
  40. A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RAR alpha mutation. Shao, W., Benedetti, L., Lamph, W.W., Nervi, C., Miller, W.H. Blood (1997) [Pubmed]
  41. The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases. Wu, W.S., Vallian, S., Seto, E., Yang, W.M., Edmondson, D., Roth, S., Chang, K.S. Mol. Cell. Biol. (2001) [Pubmed]
  42. PML-retinoic acid receptor alpha inhibits PML IV enhancement of PU.1-induced C/EBPepsilon expression in myeloid differentiation. Yoshida, H., Ichikawa, H., Tagata, Y., Katsumoto, T., Ohnishi, K., Akao, Y., Naoe, T., Pandolfi, P.P., Kitabayashi, I. Mol. Cell. Biol. (2007) [Pubmed]
  43. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. de Thé, H., Lavau, C., Marchio, A., Chomienne, C., Degos, L., Dejean, A. Cell (1991) [Pubmed]
  44. Role of SUMO in RNF4-mediated promyelocytic leukemia protein (PML) degradation: sumoylation of PML and phospho-switch control of its SUMO binding domain dissected in living cells. Percherancier, Y., Germain-Desprez, D., Galisson, F., Mascle, X.H., Dianoux, L., Estephan, P., Chelbi-Alix, M.K., Aubry, M. J. Biol. Chem. (2009) [Pubmed]
  45. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Chen, G.Q., Zhu, J., Shi, X.G., Ni, J.H., Zhong, H.J., Si, G.Y., Jin, X.L., Tang, W., Li, X.S., Xong, S.M., Shen, Z.X., Sun, G.L., Ma, J., Zhang, P., Zhang, T.D., Gazin, C., Naoe, T., Chen, S.J., Wang, Z.Y., Chen, Z. Blood (1996) [Pubmed]
  46. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Muindi, J., Frankel, S.R., Miller, W.H., Jakubowski, A., Scheinberg, D.A., Young, C.W., Dmitrovsky, E., Warrell, R.P. Blood (1992) [Pubmed]
  47. Promyelocytic leukemia protein sensitizes tumor necrosis factor alpha-induced apoptosis by inhibiting the NF-kappaB survival pathway. Wu, W.S., Xu, Z.X., Hittelman, W.N., Salomoni, P., Pandolfi, P.P., Chang, K.S. J. Biol. Chem. (2003) [Pubmed]
 
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