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Distinct interactions of PML-RARα and PLZF-RARα with co-repressors determine differential responses to RA in APL

Nature Genetics volume 18, pages 126–135 (1998)Cite this article

Abstract

Acute promyelocytic leukaemia (APL), associated with chromosomal translocations involving the retinoic acid receptor α gene (RARA) and the PML gene, is sensitive to retinoic acid (RA) treatment, while APL patients harbouring translocations between RARA and the PLZF gene do not respond to RA. We have generated PML-RARA and PLZF-RARA transgenic mice and show here that these fusion proteins play a critical role in leukaemogenesis and in determining responses to RA in APL, because PLZF-RARA transgenic mice develop RA-resistant leukaemia, while PML-RARA mice are responsive to RA treatment. We demonstrate that both PML-RARα and PLZF-RARα fusion proteins can act as transcriptional repressors and are able to interact with nuclear receptor transcriptional co-repressors, such as SMRT. PLZF-RARα, but not PML-RARα, can form, via its PLZF moiety, co-repressor complexes which are insensitive to RA. Histone deacetylase inhibitors such as Trichostatin A (TSA), in combination with RA, can overcome the transcriptional repressor activity of PML-RARα and PLZF-RARα as well as the unresponsiveness of PLZF-RARα-expressing leukaemic cells to RA. Thus, our findings unravel a crucial role for transcriptional silencing in APL pathogenesis and resistance to RA in APL.

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References

  1. Grignani, F. et al. Acute promyelocytic leukaemia: from genetics to treatment. Blood 93, 10–25 (1994).

    Google Scholar 

  2. Warrell, R.P., Jr., de The, H., Wang, Z.Y. & Degos, L. Acute promyelocytic leukaemia. N. Engl. J. Med. 329, 177–189 (1993).

    Article  CAS  Google Scholar 

  3. Pandolfi, P.P. PML, PLZF and NPM in the pathogenesis of Acute Promyelocytic Leukaemia. Haematol. 81, 472–482 (1996).

    CAS  Google Scholar 

  4. Kalantry, S. et al. Gene rearrangements in the molecular pathogenesis of Acute Promyelocytic Leukaemia. J. Cell. Phys. 173, 288–296 (1997).

    Article  CAS  Google Scholar 

  5. Pandolfi, P.P. et al. Structure and origin of the acute promyelocytic leukaemia myl/RARα cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 6, 1285–1292 (1991).

    CAS  PubMed  Google Scholar 

  6. Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukaemia fuses RARa with a novel putative transcription factor, PML. Cell 66, 663–674 (1991).

    Article  CAS  Google Scholar 

  7. de The, H. et al. The PML/RARa fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukaemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).

    Article  CAS  Google Scholar 

  8. Goddard, A.D., Borrow, J., Freemont, I. & Solomon, E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukaemia. Science 254, 1371–1374 (1991).

    Article  CAS  Google Scholar 

  9. Chen, Z. et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic luekaemia. EMBO J. 12, 1161–1167 (1993).

    Article  CAS  Google Scholar 

  10. Pandolfi, P.P. et al. Genomic variability and alternative splicings generate multiple PML/RARoc transcripts that encode aberrant PML proteins and PML/RARa isoforms in acute promyelocytic leukaemias. EMBO J. 11, 1397–1407 (1992).

    Article  CAS  Google Scholar 

  11. Reddy, B.A., Etkin, L.D. & Freemont, P.S. A novel zinc finger coiled-coil domain in a family of nuclear proteins. Trends Biochem. Sci. 17, 344–345 (1992).

    Article  CAS  Google Scholar 

  12. Li, J.Y. et al. Sequence-specific DNA binding andtranscriptional regulation by the promyelocytic leukaemia zinc finger protein. J. Biol. Chem. 272, 22447–22455 (1997).

    Article  CAS  Google Scholar 

  13. Koken, M.H.M. et al. Leukaemia-associated retinoic acid receptor alpha fusion partners, PML and PLZF, heterodimerize and colocalize to nuclear bodies [In Process Citation]. Proc. Natal. Acad. Sci. USA 94, 10255–10260 (1997).

    Article  CAS  Google Scholar 

  14. Chambon, P. A decade of molecular biology of retinoic acid receptors. Faseb J. 10, 940–954 (1996).

    Article  CAS  Google Scholar 

  15. Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 389, 349–352 (1997).

    Article  CAS  Google Scholar 

  16. Smith, M.A., Parkinson, D.R., Cheson, B.D. & Friedman, M.A. Retinoids in cancer therapy. J. Clin. Oncol. 10, 839–864 (1992).

    Article  CAS  Google Scholar 

  17. Gudas, L., Sporn, M. & Roberts, A. . in The Retinoids: Cellular biology and biochemistry of the retinoids. 443–520 (Raven Press, New-York, 1994).

  18. Fenaux, P., Chomienne, C. & Degos, L., Acute Promyelocyctic Leukaemia:Biology and Treatment. Sem. One. 24, 92–102 (1997).

    CAS  Google Scholar 

  19. Licht, J.D. et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukaemia associated with translocation (11;17). Blood 85, 1083–1094(1995).

    CAS  PubMed  Google Scholar 

  20. Perez, A. et al. PML/RAR homodimers: distinct DNA binding properties and heteromeric interactions with RXR. EMBO J. 12, 3171–3182 (1993).

    Article  CAS  Google Scholar 

  21. Jansen, J.H. et al. Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukaemia cells and interference with retinoid and peroxisome-proliferator signaling pathways.Proc. Natal. Acad. Sci. USA 92, 7401–7405 (1995).

    Article  CAS  Google Scholar 

  22. Licht, J.D. et al. Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-oc chimera generated in t(11;17)-associated acute promyelocytic leukaemia. Oncogene 12, 323–336 (1996).

    CAS  PubMed  Google Scholar 

  23. Dong, S. et al. Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukaemia zinc finger-retinoic acid receptor-a fusion protein. Proc. Natal. Acad. Sci. USA 93, 3624–3629 (1996).

    Article  CAS  Google Scholar 

  24. Kastner, P. et al. Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukaemia (APL): structural similarities with a new family of oncoproteins. EMBO J. 11, 629–642(1992).

    Article  CAS  Google Scholar 

  25. Chen, Z. et al. PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukaemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors. Proc Natal. Acad. Sci. USA 91, 1178–1182 (1994).

    Article  CAS  Google Scholar 

  26. Dyck, J. et al. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 76, 333–343 (1994).

    Article  CAS  Google Scholar 

  27. Koken, M.H.M. et al. The t(15; 17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO J. 13, 1073–1083 (1994).

    Article  CAS  Google Scholar 

  28. Weis, K. et al. Retinoic acid regulates aberrant nuclear localization of PML-RARoc in acute promyelocytic luekemic cells. Cell 76, 345–356 (1994).

    Article  CAS  Google Scholar 

  29. Nervi, C. et al. Characterization of the PML/RARa chimeric product of the acute promyelocytic leukaemia specific t(15;17) translocation. Cancer Res. 52, 3687–3692 (1992).

    CAS  PubMed  Google Scholar 

  30. Ruthardt, M. et al. Opposite effects of the acute promyelocytic leukaemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling. Mol. Cell. Biol. 17, 4859–4869 (1997).

    Article  CAS  Google Scholar 

  31. Yoshida, M., Horinouchi, S. & Beppu, T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17, 423–430 (1995).

    Article  CAS  Google Scholar 

  32. He, L.-Z. et al. Acute leukaemia with promyelocytic features in PML/RARa transgenic mice. Proc. Natal. Acad. Sci. USA 94, 5302–5307 (1997).

    Article  CAS  Google Scholar 

  33. Goldman, J.M. Chronic myeloid leukaemia. Curr. Opin. Hematol. 4, 277–285 (1997).

    Article  CAS  Google Scholar 

  34. Warrell, R.P., et al. Differentiation therapy of acute promyelocytic leukaemia with tretinoin (all-trans-retinoic acid). N. Engl. J. Med 324, 1385–1393 (1991).

    Article  Google Scholar 

  35. Castaigne, S. et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukaemia. I. Clinical results. Blood 76, 1704–1709 (1990).

    CAS  PubMed  Google Scholar 

  36. Chen, S.-J. et al. Rearrangements of the retinoic acid receptor alpha and promyelocytic leukaemia zinc finger genes resulting from t(11;17)(q23;21) in a patient with acute promyelocytic leukaemia. J. Clin. Invest. 91, 2260–2267 (1993).

    Article  CAS  Google Scholar 

  37. Jansen, J.H., de Ridder, M. C., Erpelinck, C., Geertsma, W. & de Greef, G.E. Granulocytic Differentiation of t(11;17) Positive AML-M3 Cells. Blood 88, 3421–3173 (1996).

    Google Scholar 

  38. Grisolano, J.L., Wesselschmidt, R.L., Pelicci, P.G. & Ley, T.J. Altered myeloid development and acute leukaemia in transgenic mice expressing PML-RARa under control of cathepsin G regulatory sequences. Blood 89, 376–387 (1997).

    CAS  PubMed  Google Scholar 

  39. Brown, D. et al. A PMLRARa transgene initiates murine acute promyelocytic leukaemia. Proc. Natal. Acad. Sci. USA 94, 2551–2556 (1997).

    Article  CAS  Google Scholar 

  40. Lafage-Pochitaloff, M. et al. Acute promyelocytic luekemia cases with nonreciprocal PML/RARa or RARa/PML fusion genes. Blood 85, 1169–1174 (1995).

    CAS  PubMed  Google Scholar 

  41. Hong, S.H., David, G., Wong, C.W., Dejean, A. & Privalsky, M.L. SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukaemia. Proc. Natal. Acad. Sci. USA 94, 9028–9033 (1997).

    Article  CAS  Google Scholar 

  42. Heinzel, T. et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387, 43–48 (1997).

    Article  CAS  Google Scholar 

  43. Alland, L. et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387, 49–55 (1997).

    Article  CAS  Google Scholar 

  44. Hassig, C.A., Fleischer, T.C., Billin, A.N., Schreiber, S.L. & Ayer, D.E. Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 89, 341–347(1997).

    Article  CAS  Google Scholar 

  45. Laherty, C.D. et al. Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89, 349–356 (1997).

    Article  CAS  Google Scholar 

  46. Dermime, S. et al. Occurrence of resistance to retinoic acid in the acute promyelocytic leukaemia cell line NB4 is associated with altered expression of the pml/RAR alpha protein. Blood 82, 1573–1577 (1993).

    CAS  PubMed  Google Scholar 

  47. Shao, W., Benedetti, L., Lamph, W.W., Nervi, C. & Miller Jr., W.H., A Retinoid-Resistant Acute Promyelocytic Leukaemia Subclone Expresses a Dominant Negative PML-RARa Mutation. Blood 89, 4282–4289 (1997).

    CAS  PubMed  Google Scholar 

  48. Ding, W. et al. Retinoic Acid receptor alpha (RARa)-region mutations jn the PML-RARa fusion gene of acute promyelocytic leukaemia (APL) patients after relapse from all-trans retinoic acid (ATRA) therapy, Blood 90, 415a (1997).

    Google Scholar 

  49. Lea, M.A. & Tulsyan, N. Discordant effects of butyrate analogues on erythroleukaemia cell proliferation, differentiation and histone deacetylase. Anticancer. Res. 15, 879–883 (1995).

    CAS  PubMed  Google Scholar 

  50. Darkin-Rattray, S.J. et al. Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc. Natal. Acad. Sci. USA 93, 13143–13147 (1996).

    Article  CAS  Google Scholar 

  51. Collins, A.F. et al. Oral Sodium Phenylbutyrate therapy in homozygous (3-Thalassemia: a clinical trial. Blood 85, 43–49 (1995).

    CAS  Google Scholar 

  52. Rousselot, P. et al. The PML-RAR alpha gene product of the t(15; 17) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells. Oncogene 9, 545–551 (1994).

    CAS  PubMed  Google Scholar 

  53. Horlein, A.J. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397–404 (1995).

    Article  CAS  Google Scholar 

  54. Gaub, M.P. et al. Immunodetection of multiple species of retinoic acid receptor alpha: evidence for phosphorylation. Exp. Cell Res. 201, 335–346 (1992).

    Article  CAS  Google Scholar 

  55. Borden, K.L.B. et al. The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML. EMBO J. 14, 1532–1541 (1995).

    Article  Google Scholar 

  56. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  57. Longo, L. et al. Rearrangements and aberrant expression of the RARa gene in acute promyelocytic leukaemias. J. Exp. Med. 172, 1571–1575 (1990).

    Article  CAS  Google Scholar 

  58. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular cloning: a laboratory manual. (Cold Spring Harbor Laboratory Press, Plainview, NY, 1989).

  59. Dignam, J.D., Lebovitz, R.M. & Roeder, R.G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucl. Acids. Res. 11, 1475–1489 (1983).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Human Genetics, Memorial Sloan-Kettering Cancer Center and Molecular Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, New York, 10021, USA

    Li-Zhen He, Carla Tribioli, Daniela Peruzzi & Pier Paolo Pandolfi

  2. Chester Beatty Laboratories, Leukaemia Research Fund Center at the Institute for Cancer Research, 2307 Fulham Road, London, SW3 6JB, UK

    Fabien Guidez & Arthur Zelent

  3. Istituto Oncologico Europeo, Milano, Italy

    Martin Ruthardt

  4. Department of Haematology, Med. Klinik III, J. W. Goethe- University, 7 Theodor Stern Kai, 60590, Frankfurt/Main, Germany

    Martin Ruthardt

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  1. Li-Zhen He
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  2. Fabien Guidez
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Correspondence to Pier Paolo Pandolfi.

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He, LZ., Guidez, F., Tribioli, C. et al. Distinct interactions of PML-RARα and PLZF-RARα with co-repressors determine differential responses to RA in APL. Nat Genet 18, 126–135 (1998). https://doi.org/10.1038/ng0298-126

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