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. 1992 Feb;11(2):629–642. doi: 10.1002/j.1460-2075.1992.tb05095.x

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.

P Kastner 1, A Perez 1, Y Lutz 1, C Rochette-Egly 1, M P Gaub 1, B Durand 1, M Lanotte 1, R Berger 1, P Chambon 1
PMCID: PMC556495  PMID: 1311253

Abstract

Acute promyelocytic leukemia (APL) is due to a chromosomal t(15;17) translocation which involves a novel human gene, Myl, (also named PML) and the retinoic acid (RA) receptor alpha (RAR-alpha) gene. We report here the characterization of Myl and of the reciprocal MylRAR (PMLRAR) and RARMyl (RARPML) fusion transcripts which are found in two classes of APL patients. Myl displays similarities with a new family of proteins of which some members are fused to protooncogenes in the transforming proteins RFP-ret and T18. The speckled nuclear localization of Myl, as well as its sequence homology with the 52 kDa component of the RO/SSA ribonucleoprotein particle, suggest that Myl may be present in a ribonucleoprotein complex. In contrast to both Myl and RAR-alpha whose localization is essentially nuclear in the presence or absence of RA, MylRAR which is largely cytoplasmic in the absence of RA appears to be translocated to the nucleus in the presence of RA. Myl and MylRAR can associate in vitro and this association is mediated by a coiled coil in the Myl sequence. In vivo this association results in a colocalization of Myl and MylRAR which is identical to that of MylRAR alone. Studies of activation of transcription from the promoters of several RA target genes indicate that MylRARs have altered transcription activation properties when compared with RAR-alpha. Most notably, MylRAR represses markedly the activity of some RA target promoters in the absence of RA. Western blot analyses of patient samples show that MylRAR is expressed to a much higher level than wild type RAR-alpha originating from the normal allele. Taken together, these results suggest that MylRAR may interfere in a dominant manner with both Myl and RAR functions.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alcalay M., Zangrilli D., Pandolfi P. P., Longo L., Mencarelli A., Giacomucci A., Rocchi M., Biondi A., Rambaldi A., Lo Coco F. Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1977–1981. doi: 10.1073/pnas.88.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ben-Chetrit E., Chan E. K., Sullivan K. F., Tan E. M. A 52-kD protein is a novel component of the SS-A/Ro antigenic particle. J Exp Med. 1988 May 1;167(5):1560–1571. doi: 10.1084/jem.167.5.1560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berg J. M. Zinc fingers and other metal-binding domains. Elements for interactions between macromolecules. J Biol Chem. 1990 Apr 25;265(12):6513–6516. [PubMed] [Google Scholar]
  4. Borrow J., Goddard A. D., Sheer D., Solomon E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science. 1990 Sep 28;249(4976):1577–1580. doi: 10.1126/science.2218500. [DOI] [PubMed] [Google Scholar]
  5. Brand N. J., Petkovich M., Chambon P. Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha). Nucleic Acids Res. 1990 Dec 11;18(23):6799–6806. doi: 10.1093/nar/18.23.6799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brand N., Petkovich M., Krust A., Chambon P., de Thé H., Marchio A., Tiollais P., Dejean A. Identification of a second human retinoic acid receptor. Nature. 1988 Apr 28;332(6167):850–853. doi: 10.1038/332850a0. [DOI] [PubMed] [Google Scholar]
  7. Breitman T. R., Selonick S. E., Collins S. J. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A. 1980 May;77(5):2936–2940. doi: 10.1073/pnas.77.5.2936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brockes J. P. Retinoids, homeobox genes, and limb morphogenesis. Neuron. 1989 Apr;2(4):1285–1294. doi: 10.1016/0896-6273(89)90066-4. [DOI] [PubMed] [Google Scholar]
  9. Brunk B. P., Martin E. C., Adler P. N. Drosophila genes Posterior Sex Combs and Suppressor two of zeste encode proteins with homology to the murine bmi-1 oncogene. Nature. 1991 Sep 26;353(6342):351–353. doi: 10.1038/353351a0. [DOI] [PubMed] [Google Scholar]
  10. Carmo-Fonseca M., Pepperkok R., Sproat B. S., Ansorge W., Swanson M. S., Lamond A. I. In vivo detection of snRNP-rich organelles in the nuclei of mammalian cells. EMBO J. 1991 Jul;10(7):1863–1873. doi: 10.1002/j.1460-2075.1991.tb07712.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Castaigne S., Chomienne C., Daniel M. T., Ballerini P., Berger R., Fenaux P., Degos L. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990 Nov 1;76(9):1704–1709. [PubMed] [Google Scholar]
  12. Cavener D. R., Ray S. C. Eukaryotic start and stop translation sites. Nucleic Acids Res. 1991 Jun 25;19(12):3185–3192. doi: 10.1093/nar/19.12.3185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chan E. K., Hamel J. C., Buyon J. P., Tan E. M. Molecular definition and sequence motifs of the 52-kD component of human SS-A/Ro autoantigen. J Clin Invest. 1991 Jan;87(1):68–76. doi: 10.1172/JCI115003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chen Z., Chen S. J., Tong J. H., Zhu Y. J., Huang M. E., Wang W. C., Wu Y., Sun G. L., Wang Z. Y., Larsen C. J. The retinoic acid alpha receptor gene is frequently disrupted in its 5' part in Chinese patients with acute promyelocytic leukemia. Leukemia. 1991 Apr;5(4):288–292. [PubMed] [Google Scholar]
  15. Chomienne C., Ballerini P., Balitrand N., Amar M., Bernard J. F., Boivin P., Daniel M. T., Berger R., Castaigne S., Degos L. Retinoic acid therapy for promyelocytic leukaemia. Lancet. 1989 Sep 23;2(8665):746–747. doi: 10.1016/s0140-6736(89)90812-x. [DOI] [PubMed] [Google Scholar]
  16. Clarkson B. Retinoic acid in acute promyelocytic leukemia: the promise and the paradox. Cancer Cells. 1991 Jun;3(6):211–220. [PubMed] [Google Scholar]
  17. Cleary M. L. Oncogenic conversion of transcription factors by chromosomal translocations. Cell. 1991 Aug 23;66(4):619–622. doi: 10.1016/0092-8674(91)90105-8. [DOI] [PubMed] [Google Scholar]
  18. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Forman B. M., Samuels H. H. Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. Mol Endocrinol. 1990 Sep;4(9):1293–1301. doi: 10.1210/mend-4-9-1293. [DOI] [PubMed] [Google Scholar]
  20. Freemont P. S., Hanson I. M., Trowsdale J. A novel cysteine-rich sequence motif. Cell. 1991 Feb 8;64(3):483–484. doi: 10.1016/0092-8674(91)90229-r. [DOI] [PubMed] [Google Scholar]
  21. Fu X. D., Maniatis T. Factor required for mammalian spliceosome assembly is localized to discrete regions in the nucleus. Nature. 1990 Feb 1;343(6257):437–441. doi: 10.1038/343437a0. [DOI] [PubMed] [Google Scholar]
  22. Gall J. G. Spliceosomes and snurposomes. Science. 1991 Jun 14;252(5012):1499–1500. doi: 10.1126/science.1828621. [DOI] [PubMed] [Google Scholar]
  23. Garnier J., Osguthorpe D. J., Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978 Mar 25;120(1):97–120. doi: 10.1016/0022-2836(78)90297-8. [DOI] [PubMed] [Google Scholar]
  24. Gascuel O., Golmard J. L. A simple method for predicting the secondary structure of globular proteins: implications and accuracy. Comput Appl Biosci. 1988 Aug;4(3):357–365. doi: 10.1093/bioinformatics/4.3.357. [DOI] [PubMed] [Google Scholar]
  25. Gaub M. P., Lutz Y., Ruberte E., Petkovich M., Brand N., Chambon P. Antibodies specific to the retinoic acid human nuclear receptors alpha and beta. Proc Natl Acad Sci U S A. 1989 May;86(9):3089–3093. doi: 10.1073/pnas.86.9.3089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gelman I. H., Silverstein S. Herpes simplex virus immediate-early promoters are responsive to virus and cell trans-acting factors. J Virol. 1987 Jul;61(7):2286–2296. doi: 10.1128/jvi.61.7.2286-2296.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Giguere V., Ong E. S., Segui P., Evans R. M. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. doi: 10.1038/330624a0. [DOI] [PubMed] [Google Scholar]
  28. Glass C. K., Devary O. V., Rosenfeld M. G. Multiple cell type-specific proteins differentially regulate target sequence recognition by the alpha retinoic acid receptor. Cell. 1990 Nov 16;63(4):729–738. doi: 10.1016/0092-8674(90)90139-6. [DOI] [PubMed] [Google Scholar]
  29. Green S., Chambon P. Nuclear receptors enhance our understanding of transcription regulation. Trends Genet. 1988 Nov;4(11):309–314. doi: 10.1016/0168-9525(88)90108-4. [DOI] [PubMed] [Google Scholar]
  30. Green S., Issemann I., Sheer E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucleic Acids Res. 1988 Jan 11;16(1):369–369. doi: 10.1093/nar/16.1.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Green S., Walter P., Kumar V., Krust A., Bornert J. M., Argos P., Chambon P. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986 Mar 13;320(6058):134–139. doi: 10.1038/320134a0. [DOI] [PubMed] [Google Scholar]
  32. Haupt Y., Alexander W. S., Barri G., Klinken S. P., Adams J. M. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell. 1991 May 31;65(5):753–763. doi: 10.1016/0092-8674(91)90383-a. [DOI] [PubMed] [Google Scholar]
  33. Huang M. E., Ye Y. C., Chen S. R., Chai J. R., Lu J. X., Zhoa L., Gu L. J., Wang Z. Y. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988 Aug;72(2):567–572. [PubMed] [Google Scholar]
  34. Itoh K., Itoh Y., Frank M. B. Protein heterogeneity in the human Ro/SSA ribonucleoproteins. The 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes. J Clin Invest. 1991 Jan;87(1):177–186. doi: 10.1172/JCI114968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Jones J. S., Weber S., Prakash L. The Saccharomyces cerevisiae RAD18 gene encodes a protein that contains potential zinc finger domains for nucleic acid binding and a putative nucleotide binding sequence. Nucleic Acids Res. 1988 Jul 25;16(14B):7119–7131. doi: 10.1093/nar/16.14.7119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kakizuka A., Miller W. H., Jr, Umesono K., Warrell R. P., Jr, Frankel S. R., Murty V. V., Dmitrovsky E., Evans R. M. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991 Aug 23;66(4):663–674. doi: 10.1016/0092-8674(91)90112-c. [DOI] [PubMed] [Google Scholar]
  37. Kastner P., Krust A., Mendelsohn C., Garnier J. M., Zelent A., Leroy P., Staub A., Chambon P. Murine isoforms of retinoic acid receptor gamma with specific patterns of expression. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2700–2704. doi: 10.1073/pnas.87.7.2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lanotte M., Martin-Thouvenin V., Najman S., Balerini P., Valensi F., Berger R. NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood. 1991 Mar 1;77(5):1080–1086. [PubMed] [Google Scholar]
  39. Leroy P., Krust A., Zelent A., Mendelsohn C., Garnier J. M., Kastner P., Dierich A., Chambon P. Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid. EMBO J. 1991 Jan;10(1):59–69. doi: 10.1002/j.1460-2075.1991.tb07921.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Leroy P., Nakshatri H., Chambon P. Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10138–10142. doi: 10.1073/pnas.88.22.10138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Loh E. Y., Elliott J. F., Cwirla S., Lanier L. L., Davis M. M. Polymerase chain reaction with single-sided specificity: analysis of T cell receptor delta chain. Science. 1989 Jan 13;243(4888):217–220. doi: 10.1126/science.2463672. [DOI] [PubMed] [Google Scholar]
  42. Longo L., Pandolfi P. P., Biondi A., Rambaldi A., Mencarelli A., Lo Coco F., Diverio D., Pegoraro L., Avanzi G., Tabilio A. Rearrangements and aberrant expression of the retinoic acid receptor alpha gene in acute promyelocytic leukemias. J Exp Med. 1990 Dec 1;172(6):1571–1575. doi: 10.1084/jem.172.6.1571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Lutz Y., Jacob M., Fuchs J. P. The distribution of two hnRNP-associated proteins defined by a monoclonal antibody is altered in heat-shocked HeLa cells. Exp Cell Res. 1988 Mar;175(1):109–124. doi: 10.1016/0014-4827(88)90259-5. [DOI] [PubMed] [Google Scholar]
  44. Mattei M. G., Petkovich M., Mattei J. F., Brand N., Chambon P. Mapping of the human retinoic acid receptor to the q21 band of chromosome 17. Hum Genet. 1988 Oct;80(2):186–188. doi: 10.1007/BF00702866. [DOI] [PubMed] [Google Scholar]
  45. Mendelsohn C., Ruberte E., LeMeur M., Morriss-Kay G., Chambon P. Developmental analysis of the retinoic acid-inducible RAR-beta 2 promoter in transgenic animals. Development. 1991 Nov;113(3):723–734. doi: 10.1242/dev.113.3.723. [DOI] [PubMed] [Google Scholar]
  46. Miki T., Fleming T. P., Crescenzi M., Molloy C. J., Blam S. B., Reynolds S. H., Aaronson S. A. Development of a highly efficient expression cDNA cloning system: application to oncogene isolation. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5167–5171. doi: 10.1073/pnas.88.12.5167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Mitchell P. J., Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989 Jul 28;245(4916):371–378. doi: 10.1126/science.2667136. [DOI] [PubMed] [Google Scholar]
  48. Nagpal S., Ostrove J. M. Characterization of a potent varicella-zoster virus-encoded trans-repressor. J Virol. 1991 Oct;65(10):5289–5296. doi: 10.1128/jvi.65.10.5289-5296.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Pandolfi P. P., Grignani F., Alcalay M., Mencarelli A., Biondi A., LoCoco F., Grignani F., Pelicci P. G. Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene. 1991 Jul;6(7):1285–1292. [PubMed] [Google Scholar]
  50. Patarca R., Freeman G. J., Schwartz J., Singh R. P., Kong Q. T., Murphy E., Anderson Y., Sheng F. Y., Singh P., Johnson K. A. rpt-1, an intracellular protein from helper/inducer T cells that regulates gene expression of interleukin 2 receptor and human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2733–2737. doi: 10.1073/pnas.85.8.2733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Rochette-Egly C., Lutz Y., Saunders M., Scheuer I., Gaub M. P., Chambon P. Retinoic acid receptor gamma: specific immunodetection and phosphorylation. J Cell Biol. 1991 Oct;115(2):535–545. doi: 10.1083/jcb.115.2.535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Rowley J. D., Golomb H. M., Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet. 1977 Mar 5;1(8010):549–550. doi: 10.1016/s0140-6736(77)91415-5. [DOI] [PubMed] [Google Scholar]
  53. Sawyers C. L., Denny C. T., Witte O. N. Leukemia and the disruption of normal hematopoiesis. Cell. 1991 Jan 25;64(2):337–350. doi: 10.1016/0092-8674(91)90643-d. [DOI] [PubMed] [Google Scholar]
  54. Schatz D. G., Oettinger M. A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. doi: 10.1016/0092-8674(89)90760-5. [DOI] [PubMed] [Google Scholar]
  55. Silver P. A. How proteins enter the nucleus. Cell. 1991 Feb 8;64(3):489–497. doi: 10.1016/0092-8674(91)90233-o. [DOI] [PubMed] [Google Scholar]
  56. Smith W. C., Nakshatri H., Leroy P., Rees J., Chambon P. A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter. EMBO J. 1991 Aug;10(8):2223–2230. doi: 10.1002/j.1460-2075.1991.tb07758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tagawa M., Sakamoto T., Shigemoto K., Matsubara H., Tamura Y., Ito T., Nakamura I., Okitsu A., Imai K., Taniguchi M. Expression of novel DNA-binding protein with zinc finger structure in various tumor cells. J Biol Chem. 1990 Nov 15;265(32):20021–20026. [PubMed] [Google Scholar]
  58. Takahashi M., Inaguma Y., Hiai H., Hirose F. Developmentally regulated expression of a human "finger"-containing gene encoded by the 5' half of the ret transforming gene. Mol Cell Biol. 1988 Apr;8(4):1853–1856. doi: 10.1128/mcb.8.4.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tasset D., Tora L., Fromental C., Scheer E., Chambon P. Distinct classes of transcriptional activating domains function by different mechanisms. Cell. 1990 Sep 21;62(6):1177–1187. doi: 10.1016/0092-8674(90)90394-t. [DOI] [PubMed] [Google Scholar]
  60. Tora L., White J., Brou C., Tasset D., Webster N., Scheer E., Chambon P. The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell. 1989 Nov 3;59(3):477–487. doi: 10.1016/0092-8674(89)90031-7. [DOI] [PubMed] [Google Scholar]
  61. Vallee B. L., Coleman J. E., Auld D. S. Zinc fingers, zinc clusters, and zinc twists in DNA-binding protein domains. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):999–1003. doi: 10.1073/pnas.88.3.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Warrell R. P., Jr, Frankel S. R., Miller W. H., Jr, Scheinberg D. A., Itri L. M., Hittelman W. N., Vyas R., Andreeff M., Tafuri A., Jakubowski A. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385–1393. doi: 10.1056/NEJM199105163242002. [DOI] [PubMed] [Google Scholar]
  63. Zelent A., Krust A., Petkovich M., Kastner P., Chambon P. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature. 1989 Jun 29;339(6227):714–717. doi: 10.1038/339714a0. [DOI] [PubMed] [Google Scholar]
  64. Zelent A., Mendelsohn C., Kastner P., Krust A., Garnier J. M., Ruffenach F., Leroy P., Chambon P. Differentially expressed isoforms of the mouse retinoic acid receptor beta generated by usage of two promoters and alternative splicing. EMBO J. 1991 Jan;10(1):71–81. doi: 10.1002/j.1460-2075.1991.tb07922.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. de Thé H., Chomienne C., Lanotte M., Degos L., Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990 Oct 11;347(6293):558–561. doi: 10.1038/347558a0. [DOI] [PubMed] [Google Scholar]
  66. de Thé 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 Aug 23;66(4):675–684. doi: 10.1016/0092-8674(91)90113-d. [DOI] [PubMed] [Google Scholar]
  67. van Lohuizen M., Frasch M., Wientjens E., Berns A. Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2. Nature. 1991 Sep 26;353(6342):353–355. doi: 10.1038/353353a0. [DOI] [PubMed] [Google Scholar]
  68. van Lohuizen M., Verbeek S., Scheijen B., Wientjens E., van der Gulden H., Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 1991 May 31;65(5):737–752. doi: 10.1016/0092-8674(91)90382-9. [DOI] [PubMed] [Google Scholar]

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