New insights into the cytoplasmic function of PML

Histology and Histopathology

Volumn 22, Issue 7-9, 2007, Pages 937-946

  Salomoni, Paolo ^a   Bellodi, C ^a  

^a MRC TOXICOLOGY UNIT   (United Kingdom)

Author keywords

TGFB pathway; TRIM family; Tumours; Viral infection

Indexed keywords

ARSENIC TRIOXIDE; CASEIN KINASE II; DAXX PROTEIN; FATTY ACID BINDING PROTEIN; INITIATION FACTOR 4E; INTERFERON; LEPTOMYCIN B; LEUKOCYTE ELASTASE; PROMYELOCYTIC LEUKEMIA PROTEIN; PROTEIN C JUN; PROTEIN P53; RETINOIC ACID; RETINOIC ACID RECEPTOR ALPHA; RETINOID X RECEPTOR ALPHA; SMAD ANCHOR FOR RECEPTOR ACTIVATION; SMAD2 PROTEIN; SMAD3 PROTEIN; SMAD4 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 2; TRIPARTITE MOTIF PROTEIN 5; ISOPROTEIN; MEMBRANE PROTEIN; NUCLEAR PROTEIN; ONCOPROTEIN; PML PROTEIN, HUMAN; PROMYELOCYTIC LEUKEMIA RETINOIC ACID RECEPTOR ALPHA FUSION ONCOPROTEIN; PROMYELOCYTIC LEUKEMIA-RETINOIC ACID RECEPTOR ALPHA FUSION ONCOPROTEIN; SIGNAL TRANSDUCING ADAPTOR PROTEIN; TRANSCRIPTION FACTOR; TRIM PROTEIN, HUMAN; TUMOR PROTEIN; TUMOR SUPPRESSOR PROTEIN; UNCLASSIFIED DRUG;

ALTERNATIVE RNA SPLICING; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; CANCER GROWTH; CANCER RESISTANCE; CELLULAR DISTRIBUTION; CHROMOSOME 15; CYTOPLASM; DRUG RESPONSE; DRUG TARGETING; GENE INACTIVATION; GENE LOCATION; GENETIC TRANSCRIPTION; HUMAN; LEUKEMOGENESIS; MALIGNANT TRANSFORMATION; MULTIGENE FAMILY; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; PROMYELOCYTIC LEUKEMIA; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; VIRUS INFECTION; ACTIVE TRANSPORT; ANIMAL; CELL CYCLE; CELL NUCLEUS; GENE EXPRESSION REGULATION; GENETICS; METABOLISM;

ACTIVE TRANSPORT, CELL NUCLEUS; ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ALTERNATIVE SPLICING; ANIMALS; CELL CYCLE; CELL NUCLEUS; CYTOPLASM; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; INTERFERONS; LEUKEMIA, PROMYELOCYTIC, ACUTE; MEMBRANE PROTEINS; NEOPLASM PROTEINS; NUCLEAR PROTEINS; ONCOGENE PROTEINS, FUSION; PROTEIN ISOFORMS; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TRANSFORMING GROWTH FACTOR BETA; TUMOR SUPPRESSOR PROTEINS; VIRUS DISEASES;

EID: 34447116912     PISSN: 02133911     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (80)

1. Attisano L. and Wrana J.L. (2002). Signal transduction by the TGF-beta superfamily. Science 296, 1646-1647.
2. Bellodi C., Kindle K., Bernassola F., Cossarizza A., Dinsdale D., Melino G., Heery D. and Salomoni P. (2006a). A cytoplasmic PML mutant inhibits p53 function. Cell Cycle 5, 2688-2692.
3. Bellodi C., Kindle K., Bernassola F., Dinsdale D., Cossarizza A., Melino G., Heery D. and Salomoni P. (2006b). Cytoplasmic function of mutant promyelocytic leukemia (PML) and PML-retinoic acid receptor-alpha. J. Biol. Chem. 281, 14465-14473.
4. Bernardi R., Guernah I., Jin D., Grisendi S., Alimonti A., Teruya-Feldstein J., Cordon-Cardo C., Simon M.C., Rafii S. and Pandolfi P.P. (2006). PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442, 779-785.
5. Cainarca S., Messali S., Ballabio A. and Meroni G. (1999). Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. Hum. Mol. Genet. 8, 1387-1396.
6. Cao T., Duprez E., Borden K.L., Freemont P.S. and Etkin L.D. (1998). Ret finger protein is a normal component of PML nuclear bodies and interacts directly with PML. J. Cell Sci. 111 (Pt 10), 1319-1329.
7. Chan J.Y., Chin W., Liew, C.T., Chang K.S. and Johnson P.J. (1998). Altered expression of the growth and transformation suppressor PML gene in human hepatocellular carcinomas and in hepatitis tissues. Eur. J. Cancer 34, 1015-1022.
8. Chelbi-Alix M.K., Pelicano L., Quignon F., Koken M.H., Venturini L., Stadler M., Pavlovic J., Degos L. and de The H. (1995). Induction of the PML protein by interferons in normal and APL calls. Leukemia 9, 2027-2033.
9. Cohen N., Sharma M., Kentsis A., Perez J.M., Strudwick S. and Borden K.L. (2001). PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA. EMBO J. 20, 4547-4559.
10. Condemine W., Takahashi Y., Zhu J., Puvion-Dutilleul F., Guegan S., Janin A. and de The H. (2006). Characterization of endogenous human promyelocytic leukemia isoforms. Cancer Res. 66, 6192-6198.
11. Daniel M.T., Koken M., Romagne O., Barbey S., Bazarbachi A., Stadler M., Guillernin M.C., Degos L., Chomienne, C. and de The H. (1993). PML protein expression in hematopoietic and acute promyelocytic leukemia cells. Blood 82, 1858-1867.
12. de The H., Lavau C., Marchio, A., Chomienne C., Degos L. and Dejean A. (1991). The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675-684.
13. Dellaire G., Ching R.W., Dehghani H., Ran Y. and Bazett-Jones D.P. (2006a). The number of PML nuclear bodies increases in early S phase by a fission mechanism. J. Cell Sci. 119, 1026-1033.
14. Dellaire G., Eskiw C.H., Dehghani H., Ching R.W. and Bazett-Jones D.P. (2006b). Mitotic accumulations of PML protein contribute to the re-establishment of PML nuclear bodies in G1. J. Cell Sci. 119, 1034-1042.
15. Derynck R., Akhurst R.J. and Balmain A. (2001). TGF-beta signaling in tumor suppression and cancer progression. Nat. Genet. 29, 117-129.
16. Everett R. D., Lomonte P., Sternsdorf T., van Driel R. and Orr A. (1999). Cell cycle regulation of PML modification and ND10 composition. J. Cell Sci. 112 (Pt 24), 4581-4588.
17. Everett R.D., Rechter S., Papior P., Tavalai N., Stamminger T. and Orr A. (2006). PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0. J. Virol. 80, 7995-8005.
18. Fagioli M., Alcalay M., Pandolfi P.P., Venturini L., Mencarelli A., Simeone A., Acampora D., Grignani F. and Pelicci P.G. (1992). Alternative splicing of PML transcripts predicts coexpression of several carboxy-terminally different protein isoforms. Oncogene 7, 1083-1091.
19. Fagioli M., Alcalay M., Tomassoni L., Ferrucci P.F., Mencarelli A., Riganelli D., Grignani F., Pozzan T., Nicoletti I. and Pelicci P.G. (1998). Cooperation between the RING + B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival. Oncogene 16, 2905-2913.
20. Goddard A.D., Borrow J., Freemont P.S. and Solomon E. (1991). Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 254, 1371-1374.
21. Grignani F., Ferrucci P.F., Testa U., Talamo G., Fagioli M., Alcalay M., Mencarelli A., Peschle C., Nicoletti I. and Pelicci P.G. (1993). The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74, 423-431.
22. Grisendi S. and Pandolfi P.P. (2005). NPM mutations in acute myelogenous leukemia. N. Engl. J. Med. 352, 291-292.
23. Guo A., Salomoni P., Luo J., Shih A., Zhong S., Gu W. and Paolo Pandolfi P. (2000). The function of PML in p53-dependent apoptosis. Nat. Cell. Biol. 2, 730-736.
24. Gurrieri C., Capodieci P., Bernardi R., Scaglioni P.P., Nafa K., Rush L.J., Verbel D.A., Cordon-Cardo C. and Pandolfi P.P. (2004a). Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J. Natl. Cancer Inst. 96, 269-279.
25. Gurrieri C., Nafa K., Merghoub T., Bernardi R., Capodieci P., Biondi A., Nimer S., Douer D., Cordon-Cardo C., Gallagher R. and Pandolfi P.P. (2004b). Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia. Blood 103, 2358-2362.
26. Horn E.J., Albor A., Liu Y., El-Hizawi S., Vanderbeek G.E., Babcock M., Bowden G.T., Hennings H., Lozano G., Weinberg W.C. and Kulesz-Martin M. (2004). RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties. Carcinogenesis 25, 157-167.
27. Huang W., Sun G.L., Li X.S., Cao Q., Lu Y., Jang G.S., Zhang F.Q., Chai J.R., Wang Z.Y. and Waxman S. (1993). Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood 82, 1264-1269.
28. Inman G.J. and Hill C.S. (2002). Stoichiometry of active smad-transcription factor complexes on DNA. J. Biol. Chem. 277, 51008-51016.
29. Jensen K., Shiels C. and Freemont P.S. (2001). PML protein isoforms and the RBCC/TRIM motif. Oncogene 20, 7223-7233.
30. Kakizuka A., Miller W.H. Jr., Umesono K., Warrell R.P. Jr, Frankel S.R., Murty V.V., Dmitrovsky E. and Evans R.M. (1991). Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66, 663-674.
31. Kastner P., Perez A., Lutz Y., Rochette-Egly C., Gaub M.P., Durand B., Lanotte M., Berger R. and Chambon P. (1992). Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J. 11, 629-642.
32. Kentsis A., Dwyer E.C., Perez J.M., Sharma M., Chen A., Pan Z.Q. and Borden K.L. (2001). The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E. J Mol. Biol. 312, 609-623.
33. Khan M.M., Nomura T., Chiba T., Tanaka K., Yoshida H., Mori K. and Ishii S. (2004). The fusion oncoprotein PML-RARalpha induces endoplasmic reticulum (ER)-associated degradation of N-CoR and ER stress. J. Biol. Chem. 279, 11814-11824.
34. Klugbauer S. and Rabes H.M. (1999). The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncqgene 18, 4388-4393.
35. Koken M.H., Linares-Cruz G., Quignon F., Viron A., Chelbi-Alix M.K., Sobczak-Thepot J., Juhlin L., Degos L., Calvo F. and de The H. (1995). The PML growth-suppressor has an altered expression in human oncogenesis. Oncogene 10, 1315-1324.
36. Koken M.H., Puvion-Dutilleul F., Guillemin M.C., Viron A., Linares-Cruz G., Stuurman N., de Jong L., Szostecki C., Calvo F., Chomienne C. et al. (1994). The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO J. 13, 1073-1083.
37. Kulkarni A.B., Huh C.G., Becker D., Geiser A., Lyght M., Flanders K.C., Roberts A.B., Sporn M.B., Ward J.M. and Karlsson S. (1993). Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770-774.
38. 3-induced PML or PML/retinoic acid receptor alpha degradation. J. Exp. Med. 193, 1361-1371.
39. Lane A.A. and Ley T.J. (2003). Neutrophil elastase cleaves PML-RARalpha and is important for the development of acute promyelocytic leukemia in mice. Cell 115, 305-318.
40. Lavau C., Marchio A., Fagioli M., Jansen J., Falini B., Lebon P., Grosveld F., Pandolfi P.P., Pelicci P.G. and Dejean A. (1995). The acute promyelocytic leukaemia-associated PML gene is induced by interferon. Oncogene 11, 871-876.
41. Le Douarin B., Zechel C., Garnier J.M., Lutz Y., Tora L., Pierrat P., Heery D., Gronemeyer H., Chambon P. and Losson R. (1995). The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. EMBO J. 14, 2020-2033.
42. Le X.F., Yang P. and Chang K.S. (1996). Analysis of the growth and transformation suppressor domains of promyelocytic leukemia gene, PML. J. Biol. Chem. 271, 130-135.
43. Lin H.K., Bergmann S. and Pandolfi P.P. (2004). Cytoplasmic PML function in TGF-beta signalling. Nature 431, 205-211.
44. Lin H.K., Bergmann S. and Pandolfi P.P. (2005). Deregulated TGF-beta signaling in leukemogenesis. Oncogene 24, 5693-5700.
45. Meroni G. and Diez-Roux G. (2005). TRIM/RBCC, a novel class of 'single protein RING finger' E3 ubiquitin ligases. Bioessays 27, 1147-1157.
46. Morris-Desbois C., Bochard V., Reynaud C. and Jalinot P. (1999). Interaction between the Ret finger protein and the Int-6 gene product and co-localisation into nuclear bodies. J. Cell Sci. 112 (Pt 19), 3331-3342.
47. Nisole S., Stoye J.P. and Saib A. (2005). TRIM family proteins: retroviral restriction and antiviral defence. Nat. Rev. Microbiol. 3, 799-808.
48. Nomura M. and Li E. (1998). Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393, 786-790.
49. Pandolfi P.P., Alcalay M., Fagioli M., Zangrilli D., Mencarelli A., Diverio D., Biondi A., Lo Coco F., Rambaldi A., Grignani F., Rochette-Egly C., Gaube M.P., Chambon P. and Pelici P.G. (1992). Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. EMBO J. 11, 1397-1407.
50. Pearson M., Carbone R., Sebastiani C., Cioce M., Fagioli M., Saito S., Higashimoto Y., Appella E., Minucci S. and Pandolfi P.P. and Pelici P.G. (2000). PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207-210.
51. Perez A., Kastner P., Sethi S., Lutz Y., Reibel C. and Chambon P. (1993). PMLRAR homodimers: distinct DNA binding properties and heteromeric interactions with RXR. EMBO J. 12, 3171-3182.
52. Pessah M., Prunier C., Marais J., Ferrand N., Mazars A., Lallemand F., Gauthier J.M. and Atfi A. (2001). c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity. Proc. Natl. Acad. Sci. USA 98, 6198-6203.
53. Quaderi N.A., Schweiger S., Gaudenz K., Franco B., Rugarli E.I., Berger W., Feldman G.J., Volta M., Andolfi G., Gilgenkrantz S., Marion R.W., Hennekam R.C., Opitz J.M., Muenke M., Ropers H.K. and Ballabio A. (1997). Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat. Genet. 17, 285-291.
54. Rego E.M., Wang Z.G., Peruzzi D., He L.Z., Cordon-Cardo C. and Pandolfi P.P. (2001). Role of promyelocytic leukemia (PML) protein in tumor suppression. J. Exp. Med. 193, 521-529.
55. Reymond A., Meroni G., Fantozzi A., Merla G., Cairo S., Luzi L., Riganelli D., Zanaria E., Messali S., Cainarca S., Guffanti A., Minucci S., Pelicci P.G. and Ballabio A. (2001). The tripartite motif family identifies cell compartments. EMBO J. 20, 2140-2151.
56. Salomoni P. and Pandolfi P.P. (2002). The role of PML in tumor suppression. Cell 108, 165-170.
57. Salomoni P., Bernardi R., Bergmann S., Changou A., Tuttle S. and Pandolfi P.P. (2005). The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood 105, 3686-3690.
58. Scaglioni P.P., Yung T.M., Cai L.F., Erdjument-Bromage H., Kaufman A.J., Singh B., Teruya-Feldstein J., Tempst P. and Pandolfi P.P. (2006). A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126, 269-283.
59. Schweiger S., Foerster J., Lehmann T., Suckow V., Muller Y.A., Walter G., Davies T., Porter H., van Bokhoven H., Lunt P.W., Traub P. and Ropers H.H. (1999). The Opitz syndrome gene product, MID1, associates with microtubules. Proc. Natl. Acad. Sci. USA 96, 2794-2799.
60. Seo S.R., Ferrand N., Faresse N., Prunier C., Abecassis L., Pessah M., Bourgeade M.F. and Atfi A. (2006). Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling. Mol Cell 23, 547-559.
61. Shi Y. and Massague J. (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685-700.
62. Shull M.M., Ormsby I., Kier A.B., Pawlowski S., Diebold R.J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D., Annunciata N. and Doetschman T. (1992). Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693-699.
63. Siegel P.M. and Massague J. (2003). Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat. Rev. Cancer 3, 807-821.
64. Stadler M., Chelbi-Alix M.K., Koken M.H., Venturini L., Lee C., Saib A., Quignon F., Pelicano L., Guillemin M.C., Schindler C. et al. (1995). Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element. Oncogene 11, 2565-2573.
65. Takahashi M., Inaguma Y., Hiai H. and Hirose F. (1988). Developmentally regulated expression of a human "finger"-containing gene encoded by the 5′ half of the ret transforming gene. Mol. Cell Biol. 8, 1853-1856.
66. Terris B., Baldin V., Dubois S., Degott C., Flejou J.F., Henin D. and Dejean A. (1995). PML nuclear bodies are general targets for inflammation and cell proliferation. Cancer Res. 55, 1590-1597.
67. Trotman L.C., Alimonti A., Scaglioni P.P., Koutcher J.A., Cordon-Cardo C. and Pandolli P.P. (2006). Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523-527.
68. Tsukazaki T., Chiang T.A., Davison A.F., Attisano L. and Wrana J.L. (1998). SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95, 779-791.
69. Turelli P., Doucas V., Craig E., Mangeat B., Klages N., Evans R., Kalpana G. and Trono D. (2001). Cytoplasmic recruitment of INI1 and PML on incoming HIV preintegration complexes: interference with early steps of viral replication. Mol. Cell. 7, 1245-1254.
70. Vahdat L., Maslak P., Miller W.H. Jr, Eardley A., Heller G., Scheinberg D.A. and Warrell R.P. Jr (1994). Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood 84, 3843-3849.
71. Wang Z.G., Delva L., Gaboli M., Rivi R., Giorgio M., Cordon-Cardo C., Grosveld F. and Pandolfi P.P. (1998). Role of PML in cell growth and the retinoic acid pathway. Science 279, 1547-1551.
72. Wu J.W., Fairman R., Penry J. and Shi Y. (2001). Formation of a stable heterodimer between Smad2 and Smad4. J. Biol. Chem. 276, 20688-20694.
73. Yang X., Letterio J.J., Lechleider R.J., Chen L., Hayman R., Gu H., Roberts A.B. and Deng C. (1999). Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J. 18, 1280-1291.
74. Yang X., Li C., Xu X. and Deng C. (1998). The tumor suppressor SMAD4/ DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc. Natl. Acad. Sci. USA 95, 3667-3672.
75. Zheng P., Guo Y., Niu Q., Levy D.E., Dyck J.A., Lu S., Sheiman L.A. and Liu Y. (1998). Proto-oncogene PML controls genes devoted to MHC class I antigen presentation. Nature 396, 373-376.
76. Zhong S., Muller S., Ronchetti S., Freemont P.S., Dejean A. and Pandolfi P.P. (2000a). Role of SUMO-1-modified PML in nuclear body formation. Blood 95, 2748-2752.
77. Zhong S., Salomoni P. and Pandolfi P.P. (2000b). The transcriptional role of PML and the nuclear body. Nat. Cell Biol. 2, E85-90.
78. Zhu J., Gianni M., Kopf E., Honore N., Chelbi-Alix M., Koken M., Quignon F., Rochette-Egly C. and de The H. (1999). Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RARalpha) and oncogenic RARalpha fusion proteins. Proc. Natl. Acad. Sci. USA 96, 14807-14812.
79. Zhu J., Lallemand-Breitenbach V. and de The H. (2001). Pathways of retinoic acid- or arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degradation in disease remission. Oncogene 20, 7257-7265.
80. Zhu J., Zhou J., Peres L., Riaucoux F., Honore N., Kogan S. and de The H. (2005). A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer Cell 7, 143-153.