Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

PML-mediated signaling and its role in cancer stem cells

Oncogene volume 33, pages 1475–1484 (2014)Cite this article

Subjects

Abstract

The promyelocytic leukemia (PML) protein, initially discovered as a part of the PML/retinoic acid receptor alpha fusion protein, has been found to be a critical player in oncogenesis and tumor progression. Multiple cellular activities, including DNA repair, alternative lengthening of telomeres, transcriptional control, apoptosis and senescence, are regulated by PML and its featured subcellular structure, the PML nuclear body. In correspondence with its role in many important life processes, PML mediates several complex downstream signaling pathways. The determinant function of PML in tumorigenesis and cancer progression raises the interest in its involvement in cancer stem cells (CSCs), a subpopulation of cancer cells that share properties with stem cells and are critical for tumor propagation. Recently, there are exciting discoveries concerning the requirement of PML in CSC maintenance. Growing evidences strongly suggest a positive role of PML in regulating CSCs in both hematopoietic cancers and solid tumors, whereas the underlying mechanisms may be different and remain elusive. Here we summarize and discuss the PML-mediated signaling pathways in cancers and their potential roles in regulating CSCs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A . The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 1991; 66: 675–684.

    Article  CAS  PubMed  Google Scholar 

  2. Goddard AD, Borrow J, Freemont PS, Solomon E . Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 1991; 254: 1371–1374.

    CAS  PubMed  Google Scholar 

  3. Kakizuka A, Miller WH Jr., Umesono K, Warrell RP Jr., Frankel SR, Murty VV et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 1991; 66: 663–674.

    CAS  PubMed  Google Scholar 

  4. de The H, Chen Z . Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer 2010; 10: 775–783.

    Article  CAS  PubMed  Google Scholar 

  5. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453: 1072–1078.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE et al. A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 2012; 18: 1350–1358.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Jensen K, Shiels C, Freemont PS . PML protein isoforms and the RBCC/TRIM motif. Oncogene 2001; 20: 7223–7233.

    CAS  PubMed  Google Scholar 

  8. Hatakeyama S . TRIM proteins and cancer. Nat Rev Cancer 2011; 11: 792–804.

    CAS  PubMed  Google Scholar 

  9. Bernardi R, Pandolfi PP . Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 2007; 8: 1006–1016.

    CAS  PubMed  Google Scholar 

  10. Fagioli M, Alcalay M, Pandolfi PP, Venturini L, Mencarelli A, Simeone A et al. Alternative splicing of PML transcripts predicts coexpression of several carboxy-terminally different protein isoforms. Oncogene 1992; 7: 1083–1091.

    CAS  PubMed  Google Scholar 

  11. Condemine W, Takahashi Y, Zhu J, Puvion-Dutilleul F, Guegan S, Janin A et al. Characterization of endogenous human promyelocytic leukemia isoforms. Cancer Res 2006; 66: 6192–6198.

    CAS  PubMed  Google Scholar 

  12. Chelbi-Alix MK, Pelicano L, Quignon F, Koken MH, Venturini L, Stadler M et al. Induction of the PML protein by interferons in normal and APL cells. Leukemia 1995; 9: 2027–2033.

    CAS  PubMed  Google Scholar 

  13. Lavau C, Marchio A, Fagioli M, Jansen J, Falini B, Lebon P et al. The acute promyelocytic leukaemia-associated PML gene is induced by interferon. Oncogene 1995; 11: 871–876.

    CAS  PubMed  Google Scholar 

  14. Stadler M, Chelbi-Alix MK, Koken MH, Venturini L, Lee C, Saib A et al. Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element. Oncogene 1995; 11: 2565–2573.

    CAS  PubMed  Google Scholar 

  15. Kim TK, Lee JS, Oh SY, Jin X, Choi YJ, Lee TH et al. Direct transcriptional activation of promyelocytic leukemia protein by IFN regulatory factor 3 induces the p53-dependent growth inhibition of cancer cells. Cancer Res 2007; 67: 11133–11140.

    CAS  PubMed  Google Scholar 

  16. de Stanchina E, Querido E, Narita M, Davuluri RV, Pandolfi PP, Ferbeyre G et al. PML is a direct p53 target that modulates p53 effector functions. Mol Cell 2004; 13: 523–535.

    CAS  PubMed  Google Scholar 

  17. Lapi E, Di Agostino S, Donzelli S, Gal H, Domany E, Rechavi G et al. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol Cell 2008; 32: 803–814.

    CAS  PubMed  Google Scholar 

  18. Vlasakova J, Novakova Z, Rossmeislova L, Kahle M, Hozak P, Hodny Z . Histone deacetylase inhibitors suppress IFNalpha-induced up-regulation of promyelocytic leukemia protein. Blood 2007; 109: 1373–1380.

    CAS  PubMed  Google Scholar 

  19. Hubackova S, Krejcikova K, Bartek J, Hodny Z . Interleukin 6 signaling regulates promyelocytic leukemia protein gene expression in human normal and cancer cells. J Biol Chem 2012; 287: 26702–26714.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Scaglioni PP, Rabellino A, Yung TM, Bernardi R, Choi S, Konstantinidou G et al. Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. EMBO Mol Med 2012; 4: 594–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW . PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 2000; 14: 2015–2027.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Boddy MN, Howe K, Etkin LD, Solomon E, Freemont PS . PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene 1996; 13: 971–982.

    CAS  PubMed  Google Scholar 

  23. Sternsdorf T, Jensen K, Will H . Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1. J Cell Biol 1997; 139: 1621–1634.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ET . Covalent modification of PML by the sentrin family of ubiquitin-like proteins. J Biol Chem 1998; 273: 3117–3120.

    CAS  PubMed  Google Scholar 

  25. Fu C, Ahmed K, Ding H, Ding X, Lan J, Yang Z et al. Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3. Oncogene 2005; 24: 5401–5413.

    CAS  PubMed  Google Scholar 

  26. Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem 2001; 276: 35368–35374.

    CAS  PubMed  Google Scholar 

  27. Matic I, van Hagen M, Schimmel J, Macek B, Ogg SC, Tatham MH et al. In vivo identification of human small ubiquitin-like modifier polymerization sites by high accuracy mass spectrometry and an in vitro to in vivo strategy. Mol Cell Proteomics 2008; 7: 132–144.

    CAS  PubMed  Google Scholar 

  28. Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani T, Yeh ET . Identification of three major sentrinization sites in PML. J Biol Chem 1998; 273: 26675–26682.

    CAS  PubMed  Google Scholar 

  29. Gong L, Kamitani T, Fujise K, Caskey LS, Yeh ET . Preferential interaction of sentrin with a ubiquitin-conjugating enzyme, Ubc9. J Biol Chem 1997; 272: 28198–28201.

    CAS  PubMed  Google Scholar 

  30. Desterro JM, Rodriguez MS, Kemp GD, Hay RT . Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J Biol Chem 1999; 274: 10618–10624.

    CAS  PubMed  Google Scholar 

  31. Okuma T, Honda R, Ichikawa G, Tsumagari N, Yasuda H . In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem Biophys Res Commun 1999; 254: 693–698.

    CAS  PubMed  Google Scholar 

  32. Rabellino A, Carter B, Konstantinidou G, Wu SY, Rimessi A, Byers LA et al. The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res 2012; 72: 2275–2284.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 2010; 328: 240–243.

    CAS  PubMed  Google Scholar 

  34. Gong L, Millas S, Maul GG, Yeh ET . Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J Biol Chem 2000; 275: 3355–3359.

    CAS  PubMed  Google Scholar 

  35. Best JL, Ganiatsas S, Agarwal S, Changou A, Salomoni P, Shirihai O et al. SUMO-1 protease-1 regulates gene transcription through PML. Mol Cell 2002; 10: 843–855.

    CAS  PubMed  Google Scholar 

  36. Gong L, Yeh ET . Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem 2006; 281: 15869–15877.

    CAS  PubMed  Google Scholar 

  37. Mukhopadhyay D, Ayaydin F, Kolli N, Tan SH, Anan T, Kametaka A et al. SUSP1 antagonizes formation of highly SUMO2/3-conjugated species. J Cell Biol 2006; 174: 939–949.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L et al. Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 2008; 10: 547–555.

    CAS  PubMed  Google Scholar 

  39. Percherancier Y, Germain-Desprez D, Galisson F, Mascle XH, Dianoux L, Estephan P et al. 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. J Biol Chem 2009; 284: 16595–16608.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Reineke EL, Lam M, Liu Q, Liu Y, Stanya KJ, Chang KS et al. Degradation of the tumor suppressor PML by Pin1 contributes to the cancer phenotype of breast cancer MDA-MB-231 cells. Mol Cell Biol 2008; 28: 997–1006.

    CAS  PubMed  Google Scholar 

  41. Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B et al. A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 2006; 126: 269–283.

    CAS  PubMed  Google Scholar 

  42. Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 2008; 10: 538–546.

    CAS  PubMed  Google Scholar 

  43. Geoffroy MC, Jaffray EG, Walker KJ, Hay RT . Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. Mol Biol Cell 2010; 21: 4227–4239.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T et al. E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ 2009; 16: 1156–1166.

    CAS  PubMed  Google Scholar 

  45. Wolyniec K, Shortt J, de Stanchina E, Levav-Cohen Y, Alsheich-Bartok O, Louria-Hayon I et al. E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis. Blood 2012; 120: 822–832.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Guan D, Factor D, Liu Y, Wang Z, Kao H-Y . The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein. Oncogene 2013; 32: 3819–3828.

    CAS  PubMed  Google Scholar 

  47. Yuan WC, Lee YR, Huang SF, Lin YM, Chen TY, Chung HC et al. A Cullin3-KLHL20 ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell 2011; 20: 214–228.

    CAS  PubMed  Google Scholar 

  48. Hayakawa F, Privalsky ML . Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell 2004; 5: 389–401.

    CAS  PubMed  Google Scholar 

  49. Hayakawa F, Abe A, Kitabayashi I, Pandolfi PP, Naoe T . Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis. J Biol Chem 2008; 283: 24420–24425.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lim JH, Liu Y, Reineke E, Kao HY . Mitogen-activated protein kinase extracellular signal-regulated kinase 2 phosphorylates and promotes Pin1 protein-dependent promyelocytic leukemia protein turnover. J Biol Chem 2011; 286: 44403–44411.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lallemand-Breitenbach V, de The H . PML nuclear bodies. Cold Spring Harb Perspect Biol 2010; 2: a000661.

    PubMed  PubMed Central  Google Scholar 

  52. Dyck JA, Maul GG, Miller WH Jr., Chen JD, Kakizuka A, Evans RM . A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 1994; 76: 333–343.

    CAS  PubMed  Google Scholar 

  53. Maul GG, Yu E, Ishov AM, Epstein AL . Nuclear domain 10 (ND10) associated proteins are also present in nuclear bodies and redistribute to hundreds of nuclear sites after stress. J Cell Biochem 1995; 59: 498–513.

    CAS  PubMed  Google Scholar 

  54. LaMorte VJ, Dyck JA, Ochs RL, Evans RM . Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body. Proc Natl Acad Sci USA 1998; 95: 4991–4996.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Fagioli M, Alcalay M, Tomassoni L, Ferrucci PF, Mencarelli A, Riganelli D et al. Cooperation between the RING+B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival. Oncogene 1998; 16: 2905–2913.

    CAS  PubMed  Google Scholar 

  56. Geng Y, Monajembashi S, Shao A, Cui D, He W, Chen Z et al. Contribution of the C-terminal regions of promyelocytic leukemia protein (PML) isoforms II and V to PML nuclear body formation. J Biol Chem 2012; 287: 30729–30742.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Eskiw CH, Dellaire G, Mymryk JS, Bazett-Jones DP . Size, position and dynamic behavior of PML nuclear bodies following cell stress as a paradigm for supramolecular trafficking and assembly. J Cell Sci 2003; 116: 4455–4466.

    CAS  PubMed  Google Scholar 

  58. Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T et al. PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. J Cell Biol 1999; 147: 221–234.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhong S, Muller S, Ronchetti S, Freemont PS, Dejean A, Pandolfi PP . Role of SUMO-1-modified PML in nuclear body formation. Blood 2000; 95: 2748–2752.

    CAS  PubMed  Google Scholar 

  60. Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP . The mechanisms of PML-nuclear body formation. Mol Cell 2006; 24: 331–339.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Boddy MN, Duprez E, Borden KL, Freemont PS . Surface residue mutations of the PML RING finger domain alter the formation of nuclear matrix-associated PML bodies. J Cell Sci 1997; 110 (Pt 18): 2197–2205.

    CAS  PubMed  Google Scholar 

  62. Zhong S, Hu P, Ye TZ, Stan R, Ellis NA, Pandolfi PP . A role for PML and the nuclear body in genomic stability. Oncogene 1999; 18: 7941–7947.

    CAS  PubMed  Google Scholar 

  63. Boisvert FM, Hendzel MJ, Bazett-Jones DP . Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. J Cell Biol 2000; 148: 283–292.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang J, Shiels C, Sasieni P, Wu PJ, Islam SA, Freemont PS et al. Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions. J Cell Biol 2004; 164: 515–526.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M et al. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993; 74: 423–431.

    CAS  PubMed  Google Scholar 

  66. Welch JS, Yuan W, Ley TJ . PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice. J Clin Invest 2011; 121: 1636–1645.

    PubMed  PubMed Central  Google Scholar 

  67. Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C et al. Role of PML in cell growth and the retinoic acid pathway. Science 1998; 279: 1547–1551.

    CAS  PubMed  Google Scholar 

  68. Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 2008; 14: 1333–1342.

    CAS  PubMed  Google Scholar 

  69. Carracedo A, Weiss D, Leliaert AK, Bhasin M, de Boer VC, Laurent G et al. A metabolic prosurvival role for PML in breast cancer. J Clin Invest 2012; 122: 3088–3100.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Aoto T, Saitoh N, Ichimura T, Niwa H, Nakao M . Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation. Dev Biol 2006; 298: 354–367.

    CAS  PubMed  Google Scholar 

  71. Gupta P, Ho PC, Huq MM, Ha SG, Park SW, Khan AA et al. Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression. Proc Natl Acad Sci USA 2008; 105: 11424–11429.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Park SW, Hu X, Gupta P, Lin YP, Ha SG, Wei LN . SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells. Nat Struct Mol Biol 2007; 14: 68–75.

    CAS  PubMed  Google Scholar 

  73. Kawasaki A, Matsumura I, Kataoka Y, Takigawa E, Nakajima K, Kanakura Y . Opposing effects of PML and PML/RAR alpha on STAT3 activity. Blood 2003; 101: 3668–3673.

    CAS  PubMed  Google Scholar 

  74. Liang J, Wan M, Zhang Y, Gu P, Xin H, Jung SY et al. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat Cell Biol 2008; 10: 731–739.

    CAS  PubMed  Google Scholar 

  75. Zhang P, Pazin MJ, Schwartz CM, Becker KG, Wersto RP, Dilley CM et al. Nontelomeric TRF2-REST interaction modulates neuronal gene silencing and fate of tumor and stem cells. Curr Biol 2008; 18: 1489–1494.

    PubMed  PubMed Central  Google Scholar 

  76. Smith KP, Byron M, O’Connell BC, Tam R, Schorl C, Guney I et al. c-Myc localization within the nucleus: evidence for association with the PML nuclear body. J Cell Biochem 2004; 93: 1282–1296.

    CAS  PubMed  Google Scholar 

  77. Chuang YS, Huang WH, Park SW, Persaud SD, Hung CH, Ho PC et al. Promyelocytic leukemia protein in retinoic acid-induced chromatin remodeling of Oct4 gene promoter. Stem Cells 2011; 29: 660–669.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Butler JT, Hall LL, Smith KP, Lawrence JB . Changing nuclear landscape and unique PML structures during early epigenetic transitions of human embryonic stem cells. J Cell Biochem 2009; 107: 609–621.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Li W, Ferguson BJ, Khaled WT, Tevendale M, Stingl J, Poli V et al. PML depletion disrupts normal mammary gland development and skews the composition of the mammary luminal cell progenitor pool. Proc Natl Acad Sci USA 2009; 106: 4725–4730.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Regad T, Bellodi C, Nicotera P, Salomoni P . The tumor suppressor Pml regulates cell fate in the developing neocortex. Nat Neurosci 2009; 12: 132–140.

    CAS  PubMed  Google Scholar 

  81. Carbone R, Pearson M, Minucci S, Pelicci PG . PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage. Oncogene 2002; 21: 1633–1640.

    CAS  PubMed  Google Scholar 

  82. Wu G, Lee WH, Chen PL . NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres. J Biol Chem 2000; 275: 30618–30622.

    CAS  PubMed  Google Scholar 

  83. Bischof O, Kim SH, Irving J, Beresten S, Ellis NA, Campisi J . Regulation and localization of the Bloom syndrome protein in response to DNA damage. J Cell Biol 2001; 153: 367–380.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Xu ZX, Timanova-Atanasova A, Zhao RX, Chang KS . PML colocalizes with and stabilizes the DNA damage response protein TopBP1. Mol Cell Biol 2003; 23: 4247–4256.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Barr SM, Leung CG, Chang EE, Cimprich KA . ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation. Curr Biol 2003; 13: 1047–1051.

    CAS  PubMed  Google Scholar 

  86. Park J, Seo T, Kim H, Choe J . Sumoylation of the novel protein hRIP{beta} is involved in replication protein A deposition in PML nuclear bodies. Mol Cell Biol 2005; 25: 8202–8214.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Boe SO, Haave M, Jul-Larsen A, Grudic A, Bjerkvig R, Lonning PE . Promyelocytic leukemia nuclear bodies are predetermined processing sites for damaged DNA. J Cell Sci 2006; 119: 3284–3295.

    PubMed  Google Scholar 

  88. Dellaire G, Ching RW, Ahmed K, Jalali F, Tse KC, Bristow RG et al. Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR. J Cell Biol 2006; 175: 55–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yeung PL, Denissova NG, Nasello C, Hakhverdyan Z, Chen JD, Brenneman MA . Promyelocytic leukemia nuclear bodies support a late step in DNA double-strand break repair by homologous recombination. J Cell Biochem 2012; 113: 1787–1799.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Silvestre DC, Pineda JR, Hoffschir F, Studler JM, Mouthon MA, Pflumio F et al. Alternative lengthening of telomeres in human glioma stem cells. Stem Cells 2011; 29: 440–451.

    CAS  PubMed  Google Scholar 

  91. Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR . Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res 1999; 59: 4175–4179.

    CAS  PubMed  Google Scholar 

  92. Grobelny JV, Godwin AK, Broccoli D . ALT-associated PML bodies are present in viable cells and are enriched in cells in the G(2)/M phase of the cell cycle. J Cell Sci 2000; 113 (Pt 24): 4577–4585.

    CAS  PubMed  Google Scholar 

  93. Chung I, Leonhardt H, Rippe K . De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation. J Cell Sci 2011; 124: 3603–3618.

    CAS  PubMed  Google Scholar 

  94. Nabetani A, Yokoyama O, Ishikawa F . Localization of hRad9, hHus1, hRad1, and hRad17 and caffeine-sensitive DNA replication at the alternative lengthening of telomeres-associated promyelocytic leukemia body. J Biol Chem 2004; 279: 25849–25857.

    CAS  PubMed  Google Scholar 

  95. Fasching CL, Neumann AA, Muntoni A, Yeager TR, Reddel RR . DNA damage induces alternative lengthening of telomeres (ALT) associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA. Cancer Res 2007; 67: 7072–7077.

    CAS  PubMed  Google Scholar 

  96. Draskovic I, Arnoult N, Steiner V, Bacchetti S, Lomonte P, Londono-Vallejo A . Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination. Proc Natl Acad Sci USA 2009; 106: 15726–15731.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Brouwer AK, Schimmel J, Wiegant JC, Vertegaal AC, Tanke HJ, Dirks RW . Telomeric DNA mediates de novo PML body formation. Mol Biol Cell 2009; 20: 4804–4815.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Hsu JK, Lin T, Tsai RY . Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1. J Cell Biol 2012; 197: 613–624.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Slatter TL, Tan X, Yuen YC, Gunningham S, Ma SS, Daly E et al. The alternative lengthening of telomeres pathway may operate in non-neoplastic human cells. J Pathol 2012; 226: 509–518.

    CAS  PubMed  Google Scholar 

  100. Vallian S, Chin KV, Chang KS . The promyelocytic leukemia protein interacts with Sp1 and inhibits its transactivation of the epidermal growth factor receptor promoter. Mol Cell Biol 1998; 18: 7147–7156.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Alcalay M, Tomassoni L, Colombo E, Stoldt S, Grignani F, Fagioli M et al. The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein. Mol Cell Biol 1998; 18: 1084–1093.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T et al. Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Mol Cell 2001; 7: 1233–1243.

    CAS  PubMed  Google Scholar 

  103. Wu WS, Xu ZX, Chang KS . The promyelocytic leukemia protein represses A20-mediated transcription. J Biol Chem 2002; 277: 31734–31739.

    CAS  PubMed  Google Scholar 

  104. Wu WS, Xu ZX, Ran R, Meng F, Chang KS . Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. Oncogene 2002; 21: 3925–3933.

    CAS  PubMed  Google Scholar 

  105. Vallian S, Gaken JA, Gingold EB, Kouzarides T, Chang KS, Farzaneh F . Modulation of Fos-mediated AP-1 transcription by the promyelocytic leukemia protein. Oncogene 1998; 16: 2843–2853.

    CAS  PubMed  Google Scholar 

  106. Li H, Leo C, Zhu J, Wu X, O’Neil J, Park EJ et al. Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. Mol Cell Biol 2000; 20: 1784–1796.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lehembre F, Muller S, Pandolfi PP, Dejean A . Regulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene 2001; 20: 1–9.

    CAS  PubMed  Google Scholar 

  108. Shtutman M, Zhurinsky J, Oren M, Levina E, Ben-Ze’ev A . PML is a target gene of beta-catenin and plakoglobin, and coactivates beta-catenin-mediated transcription. Cancer Res 2002; 62: 5947–5954.

    CAS  PubMed  Google Scholar 

  109. Salomoni P, Bernardi R, Bergmann S, Changou A, Tuttle S, Pandolfi PP . The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood 2005; 105: 3686–3690.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Shima Y, Shima T, Chiba T, Irimura T, Pandolfi PP, Kitabayashi I . PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated degradation. Mol Cell Biol 2008; 28: 7126–7138.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Ulbricht T, Alzrigat M, Horch A, Reuter N, von Mikecz A, Steimle V et al. PML promotes MHC class II gene expression by stabilizing the class II transactivator. J Cell Biol 2012; 199: 49–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu WS, Vallian S, Seto E, Yang WM, Edmondson D, Roth S et al. The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases. Mol Cell Biol 2001; 21: 2259–2268.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Cho S, Park JS, Kang YK . Dual functions of histone-lysine N-methyltransferase Setdb1 protein at promyelocytic leukemia-nuclear body (PML-NB): maintaining PML-NB structure and regulating the expression of its associated genes. J Biol Chem 2011; 286: 41115–41124.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R et al. PML is essential for multiple apoptotic pathways. Nat Genet 1998; 20: 266–272.

    CAS  PubMed  Google Scholar 

  115. Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC, de The H . PML induces a novel caspase-independent death process. Nat Genet 1998; 20: 259–265.

    CAS  PubMed  Google Scholar 

  116. Morgan M, Thorburn J, Pandolfi PP, Thorburn A . Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms. J Cell Biol 2002; 157: 975–984.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Yang S, Kuo C, Bisi JE, Kim MK . PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol 2002; 4: 865–870.

    CAS  PubMed  Google Scholar 

  118. Yang S, Jeong JH, Brown AL, Lee CH, Pandolfi PP, Chung JH et al. Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation. J Biol Chem 2006; 281: 26645–26654.

    CAS  PubMed  Google Scholar 

  119. Lin HK, Bergmann S, Pandolfi PP . Cytoplasmic PML function in TGF-beta signalling. Nature 2004; 431: 205–211.

    CAS  PubMed  Google Scholar 

  120. Wu WS, Xu ZX, Hittelman WN, Salomoni P, Pandolfi PP, Chang KS . Promyelocytic leukemia protein sensitizes tumor necrosis factor alpha-induced apoptosis by inhibiting the NF-kappaB survival pathway. J Biol Chem 2003; 278: 12294–12304.

    CAS  PubMed  Google Scholar 

  121. Shin J, Park B, Cho S, Lee S, Kim Y, Lee SO et al. Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase. J Biol Chem 2004; 279: 40994–41003.

    CAS  PubMed  Google Scholar 

  122. Crowder C, Dahle O, Davis RE, Gabrielsen OS, Rudikoff S . PML mediates IFN-alpha-induced apoptosis in myeloma by regulating TRAIL induction. Blood 2005; 105: 1280–1287.

    CAS  PubMed  Google Scholar 

  123. Herzer K, Hofmann TG, Teufel A, Schimanski CC, Moehler M, Kanzler S et al. IFN-alpha-induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res 2009; 69: 855–862.

    CAS  PubMed  Google Scholar 

  124. Meinecke I, Cinski A, Baier A, Peters MA, Dankbar B, Wille A et al. Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc Natl Acad Sci USA 2007; 104: 5073–5078.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Renner F, Moreno R, Schmitz ML . SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death. Mol Cell 2010; 37: 503–515.

    CAS  PubMed  Google Scholar 

  126. Fogal V, Gostissa M, Sandy P, Zacchi P, Sternsdorf T, Jensen K et al. Regulation of p53 activity in nuclear bodies by a specific PML isoform. Embo J 2000; 19: 6185–6195.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W et al. The function of PML in p53-dependent apoptosis. Nat Cell Biol 2000; 2: 730–736.

    CAS  PubMed  Google Scholar 

  128. Bao-Lei T, Zhu-Zhong M, Yi S, Jun-Jie Q, Yan D, Hua L et al. Knocking down PML impairs p53 signaling transduction pathway and suppresses irradiation induced apoptosis in breast carcinoma cell MCF-7. J Cell Biochem 2006; 97: 561–571.

    PubMed  Google Scholar 

  129. Pearson M, Pelicci PG . PML interaction with p53 and its role in apoptosis and replicative senescence. Oncogene 2001; 20: 7250–7256.

    CAS  PubMed  Google Scholar 

  130. Haupt S, di Agostino S, Mizrahi I, Alsheich-Bartok O, Voorhoeve M, Damalas A et al. Promyelocytic leukemia protein is required for gain of function by mutant p53. Cancer Res 2009; 69: 4818–4826.

    CAS  PubMed  Google Scholar 

  131. D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol 2002; 4: 11–19.

    CAS  PubMed  Google Scholar 

  132. Hofmann TG, Moller A, Sirma H, Zentgraf H, Taya Y, Droge W et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol 2002; 4: 1–10.

    CAS  PubMed  Google Scholar 

  133. Moller A, Sirma H, Hofmann TG, Rueffer S, Klimczak E, Droge W et al. PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. Cancer Res 2003; 63: 4310–4314.

    PubMed  Google Scholar 

  134. Li Q, He Y, Wei L, Wu X, Wu D, Lin S et al. AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation. Oncogene 2011; 30: 1194–1204.

    CAS  PubMed  Google Scholar 

  135. Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. Embo J 2002; 21: 2383–2396.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, Pandolfi PP, Haupt Y . The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem 2003; 278: 33134–33141.

    CAS  PubMed  Google Scholar 

  137. Zhu H, Wu L, Maki CG . MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53. J Biol Chem 2003; 278: 49286–49292.

    CAS  PubMed  Google Scholar 

  138. Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP . PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 2004; 6: 665–672.

    CAS  PubMed  Google Scholar 

  139. Wei X, Yu ZK, Ramalingam A, Grossman SR, Yu JH, Bloch DB et al. Physical and functional interactions between PML and MDM2. J Biol Chem 2003; 278: 29288–29297.

    CAS  PubMed  Google Scholar 

  140. Yang Q, Liao L, Deng X, Chen R, Gray NS, Yates JR III et al. BMK1 is involved in the regulation of p53 through disrupting the PML–MDM2 interaction. Oncogene 2013; 32: 3156–3164.

    CAS  PubMed  Google Scholar 

  141. Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP . Identification of a tumour suppressor network opposing nuclear Akt function. Nature 2006; 441: 523–527.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Culjkovic B, Tan K, Orolicki S, Amri A, Meloche S, Borden KL . The eIF4E RNA regulon promotes the Akt signaling pathway. J Cell Biol 2008; 181: 51–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 2008; 455: 813–817.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M et al. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 2010; 330: 1247–1251.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Torii S, Egan DA, Evans RA, Reed JC . Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). Embo J 1999; 18: 6037–6049.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhong S, Salomoni P, Ronchetti S, Guo A, Ruggero D, Pandolfi PP . Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J Exp Med 2000; 191: 631–640.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lin DY, Huang YS, Jeng JC, Kuo HY, Chang CC, Chao TT et al. Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell 2006; 24: 341–354.

    CAS  PubMed  Google Scholar 

  148. Lin DY, Lai MZ, Ann DK, Shih HM . Promyelocytic leukemia protein (PML) functions as a glucocorticoid receptor co-activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its transactivation potential. J Biol Chem 2003; 278: 15958–15965.

    CAS  PubMed  Google Scholar 

  149. Croxton R, Puto LA, de Belle I, Thomas M, Torii S, Hanaii F et al. Daxx represses expression of a subset of antiapoptotic genes regulated by nuclear factor-kappaB. Cancer Res 2006; 66: 9026–9035.

    CAS  PubMed  Google Scholar 

  150. Kawai T, Akira S, Reed JC . ZIP kinase triggers apoptosis from nuclear PML oncogenic domains. Mol Cell Biol 2003; 23: 6174–6186.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000; 406: 207–210.

    CAS  PubMed  Google Scholar 

  152. Condemine W, Takahashi Y, Le Bras M, de The H . A nucleolar targeting signal in PML-I addresses PML to nucleolar caps in stressed or senescent cells. J Cell Sci 2007; 120: 3219–3227.

    CAS  PubMed  Google Scholar 

  153. Bischof O, Kirsh O, Pearson M, Itahana K, Pelicci PG, Dejean A . Deconstructing PML-induced premature senescence. Embo J 2002; 21: 3358–3369.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Peche LY, Scolz M, Ladelfa MF, Monte M, Schneider C . MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs. Cell Death Differ 2012; 19: 926–936.

    CAS  PubMed  Google Scholar 

  155. Takahashi K, Yoshida N, Murakami N, Kawata K, Ishizaki H, Tanaka-Okamoto M et al. Dynamic regulation of p53 subnuclear localization and senescence by MORC3. Mol Biol Cell 2007; 18: 1701–1709.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Mallette FA, Goumard S, Gaumont-Leclerc MF, Moiseeva O, Ferbeyre G . Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence. Oncogene 2004; 23: 91–99.

    CAS  PubMed  Google Scholar 

  157. Fang W, Mori T, Cobrinik D . Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants. Oncogene 2002; 21: 5557–5565.

    CAS  PubMed  Google Scholar 

  158. Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 2005; 8: 19–30.

    CAS  PubMed  Google Scholar 

  159. Ye X, Zerlanko B, Kennedy A, Banumathy G, Zhang R, Adams PD . Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol Cell 2007; 27: 183–196.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Ye X, Zerlanko B, Zhang R, Somaiah N, Lipinski M, Salomoni P et al. Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci. Mol Cell Biol 2007; 27: 2452–2465.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Martin N, Benhamed M, Nacerddine K, Demarque MD, van Lohuizen M, Dejean A et al. Physical and functional interaction between PML and TBX2 in the establishment of cellular senescence. Embo J 2011; 31: 95–109.

    PubMed  PubMed Central  Google Scholar 

  162. Vernier M, Bourdeau V, Gaumont-Leclerc MF, Moiseeva O, Begin V, Saad F et al. Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev 2011; 25: 41–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer 2012; 12: 767–775.

    CAS  PubMed  Google Scholar 

  164. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444: 756–760.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Cleveland Clinic Foundation and a NIH R01 Grant (NS070315) to SB. We thank other members in the Bao’s lab for helpful discussion. We apologize for not including all PML references in this review due to space limit.

Author information

Authors and Affiliations

  1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    W Zhou & S Bao

Authors
  1. W Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Bao.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, W., Bao, S. PML-mediated signaling and its role in cancer stem cells. Oncogene 33, 1475–1484 (2014). https://doi.org/10.1038/onc.2013.111

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.111

Keywords

This article is cited by

Search

Advanced search

Quick links