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.

  • Original Manuscript
  • Published:

APL

Analysis of p73 expression pattern in acute myeloid leukemias: lack of ΔN-p73 expression is a frequent feature of acute promyelocytic leukemia

Leukemia volume 18, pages 1804–1809 (2004)Cite this article

Abstract

p73, the homologue of p53, is a nuclear protein whose ectopic expression, in p53+/+ and p53−/− cells, recapitulates the most well-characterized p53 effects, such as growth arrest, apoptosis and differentiation. Unlike p53, which is mutated in half of human cancers, p73 is rarely mutated. However, altered expression of the p73 gene has been reported in neuroblastoma, lung cancer, prostate cancer and renal cell carcinoma. To investigate the potential involvement of p73 in acute myeloid leukemias (AMLs), we analyzed 71 samples from AML patients for the expression pattern of N-terminal transactivation-p73α (TA-p73α), its spliced isoforms and N-terminal-deleted-p73 transcripts (ΔN-p73). We detected p73 gene expression in AML irrespective of FAB (French–American–British) subtypes. Notably, the analysis of ΔN-p73 expression, which has been reported to inactivate both p53 and p73 antitumor effects, revealed a rather peculiar pattern. In fact, ΔN-p73 transcript and protein were detectable in 27/28 (96.4%) cases of M0, M1, M2, M4, M5 and M6 AML and in 13/41 (31.7%) cases of PML-RARα-positive M3 AML (P<0.01). Thus, the distinct gene expression profile of p73 further supports the notion that acute promyelocytic leukemia is a biologically different subset of AML.

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. Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997; 90: 809–819.

    Article  CAS  Google Scholar 

  2. Arrowsmith CH . Structure and function in the p53 family. Cell Death Differ 1999; 6: 1169–1173.

    Article  CAS  Google Scholar 

  3. Chi S-W, Ayed A, Arrowsmith CH . Solution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain. EMBO J 1999; 18: 4438–4445.

    Article  CAS  Google Scholar 

  4. De Laurenzi V, Catani VM, Terrinoni A, Corazzari M, Melino G, Costanzo A et al. Additional complexity in p73: induction by mitogens in lymphoid cells and identification of two new splice variants epsilon and zeta. Cell Death Differ 1999; 6: 389–390.

    Article  CAS  Google Scholar 

  5. Ueda Y, Hijikata M, Takagi S, Chiba T, Shimotohno K . New p73 variants with altered C-terminal structures have varied transcriptional activities. Oncogene 1999; 18: 4993–4998.

    Article  CAS  Google Scholar 

  6. De Laurenzi V, Costanzo A, Barcaroli D, Terrinoni A, Falco M, Annicchiarico-Petruzzelli M et al. Two new p73 splice variants, gamma and delta, with different transcriptional activity. J Exp Med 1998; 188: 1763–1768.

    Article  CAS  Google Scholar 

  7. Scaruffi P, Casciano I, Masiero L, Basso G, Romani M, Tonini GP . Lack of p73 expression in mature B-ALL and identification of three new splicing variants restricted to pre B and C-ALL indicate a role of p73 in B cell ALL. Leukemia 2000; 14: 518–525.

    Article  CAS  Google Scholar 

  8. Zaika A, Kovalev S, Marchenko ND, Moll UM . Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res 1999; 59: 3257–3263.

    CAS  PubMed  Google Scholar 

  9. Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin C et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 2000; 404: 99–103.

    Article  CAS  Google Scholar 

  10. Kartasheva NN, Contente A, Lenz-Stoppler C, Roth J, Dobbelstein M . p53 induces the expression of its antagonist p73 Delta N, establishing an autoregulatory feedback loop. Oncogene 2002; 18: 4715–4727.

    Article  Google Scholar 

  11. Grob TJ, Novak U, Maisse C, Barcaroli D, Luthi AU, Pirnia F et al. Human deltaNp73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ 2001; 8: 1213–1223.

    Article  CAS  Google Scholar 

  12. Zaika AI, Slade N, Erster SH, Sansome C, Joseph TW, Pearl M et al. DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. J Exp Med 2002; 196: 765–780.

    Article  CAS  Google Scholar 

  13. Nakagawa T, Takahashi M, Ozaki T, Watanabe Ki K, Todo S, Mizuguchi H et al. Autoinhibitory regulation of p73 by DeltaNp73 to modulate cell survival and death through a p73-specific target element within the DeltaNp73 promoter. Mol Cell Biol 2002; 22: 2575–2585.

    Article  CAS  Google Scholar 

  14. Jost CA, Marin MC, Kaelin WG . p73 is a human p53 related protein that can induce apoptosis. Nature 1997; 389: 191–194.

    Article  CAS  Google Scholar 

  15. Stiewe T, Pulzer BM . Role of p73 in malignancy: tumor suppressor or oncogene? Cell Death Differ 2002; 9: 237–243.

    Article  CAS  Google Scholar 

  16. De Laurenzi V, Raschellà G, Barcaroli D, Annichiarico-Petruzzelli M, Ranalli M, Catani MV et al. Induction of neuronal differentiation by p73 in a neuroblastoma cell line. J Biol Chem 2000; 275: 15226–15231.

    Article  CAS  Google Scholar 

  17. Fontemaggi G, Kela I, Amariglio N, Rechavi G, Krishnamurthy J, Strano S et al. Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses. J Biol Chem 2002; 277: 43359–43368.

    Article  CAS  Google Scholar 

  18. Kaelin J . The p53 family. Oncogene 1999; 18: 7701–7705.

    Article  CAS  Google Scholar 

  19. Kong XT, Valentine VA, Rowe ST, Valentine MB, Ragsdale ST, Jones BG et al. Lack of homozygously inactivated p73 in single-copy MYCN primary neuroblastomas and neuroblastoma cell lines. Neoplasia 1999; 1: 80–89.

    Article  CAS  Google Scholar 

  20. Kovalev S, Marchenko N, Swendeman S, LaQuaglia M, Moll UM . Expression level, allelic origin, and mutation analysis of the p73 gene in neuroblastoma tumors and cell lines. Cell Growth Differ 1998; 9: 897–903.

    CAS  PubMed  Google Scholar 

  21. Stirewalt DL, Clurman B, Appelbaum FR, Willman CL, Radich JP . P73 mutations and expression in adult de novo acute myelogenous leukemia. Leukemia 1999; 13: 985–990.

    Article  CAS  Google Scholar 

  22. Morena AR, Riccioni S, Marchetti A, Tartaglia Polcini A, Mercurio AM, Blandino G et al. Expression of β4 integrin subunit induces monocytic differentiation of 32D/v-Abl cells. Blood 2002; 100: 96–106.

    Article  CAS  Google Scholar 

  23. Fontemaggi G, Gurtner A, Strano S, Higashi Y, Sacchi A, Piaggio G et al. The transcriptional repressor ZEB regulates p73 expression at the cross-road between proliferation and differentiation. Mol Cell Biol 2001; 24: 8461–8470.

    Article  Google Scholar 

  24. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative Group. Ann Intern Med 1985; 103: 620–625.

    Article  CAS  Google Scholar 

  25. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. on behalf of the Medical Research Council Adult and Children's Leukaemia Working Parties. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. Blood 1998; 92: 2322–2333.

    CAS  Google Scholar 

  26. Chomczynski P, Sacchi N . Single step method of RNA isolation by acid guanidium thiocyanate−phenol chloroform extraction. Anal Biochem 1987; 162: 156–159.

    Article  CAS  Google Scholar 

  27. Van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 1999; 13: 1901–1928.

    Article  CAS  Google Scholar 

  28. Gabbianelli M, Sargiacomo M, Pelosi E, Testa U, Isacchi G, Peschle C . ‘Pure’ human hematopoietic progenitors: permissive action of basic fibroblast growth factor. Science 1990; 249: 1561–1564.

    Article  CAS  Google Scholar 

  29. Tschan MP, Grob TJ, Peters UR, De Laurenzi V, Huegli B, Kreuzer KA et al. Enhanced p73 expression during differentiation and complex p73 isoforms in myeloid leukemia. Biochem Biophy Res Commun 2000; 277: 62–65.

    Article  CAS  Google Scholar 

  30. Peters UR, Tschan MP, Krenzer KA, Baskaynak G, Lass U, Tobler A et al. Distinct expression patterns of the p53-Homologue p73 in malignant and normal hematopoiesis assessed by a novel real-time reverse transcription-polymerase chain reaction assay and protein analysis. Cancer Res 1999; 59: 4233–4236.

    CAS  PubMed  Google Scholar 

  31. Strano S, Munarriz E, Rossi M, Cristofanelli B, Shaul Y, Castagnoli L et al. Physical and functional interaction between p53 mutants and different isoforms of p73. J Biol Chem 2000; 275: 29503–29512.

    Article  CAS  Google Scholar 

  32. Levrero M, De Laurenzi V, Costanzo A, Sabatini S, Gong J, Wang JYJ et al. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci 2000; 113: 1661–1670.

    CAS  PubMed  Google Scholar 

  33. Takagi S, Ueda Y, Hijikata M, Shimonoto K . Overproduced p73α activates a minimal promoter through a mechanism independent of its transcriptional activity. FEBS Lett 2001; 509: 47–52.

    Article  CAS  Google Scholar 

  34. Strano S, Munarriz E, Rossi M, Cristofanelli B, Castagnoli L, Shaul Y et al. Physical interaction with Yes-associated protein (YAP) enhances p73 transcriptional activity. J Biol Chem 2001; 276: 15164–15173.

    Article  CAS  Google Scholar 

  35. Basu S, Totty NF, Irwin MS, Sudol M, Downward J . Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell 2003; 11: 11–23.

    Article  CAS  Google Scholar 

  36. Vossio S, Palescandolo E, Pediconi N, Moretti F, Balsano C, Levrero M et al. DN-p73 is activated after DNA damage in a p53-dependent manner to regulate p53-induced cell cycle arrest. Oncogene 2002; 21: 3796–3803.

    Article  CAS  Google Scholar 

  37. Petrenko O, Zaika A, Moll UM . deltaNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo. Mol Cell Biol 2003; 23: 5540–5555.

    Article  CAS  Google Scholar 

  38. Tallman MS, Nabhan CH, Feusner JH, Rowe JM . Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002; 99: 759–767.

    Article  CAS  Google Scholar 

  39. Longo L, Trecca D, Biondi A, Lo Coco F, Grignani F, Maiolo AT et al. Frequency of RAS and p53 mutations in acute promyelocytic leukemias. Leukemia Lymphoma 1993; 11: 405–410.

    Article  CAS  Google Scholar 

  40. Trecca D, Longo L, Biondi A, Cro L, Calori R, Grignani F et al. Analysis of p53 gene mutations in acute myeloid leukemia. Am J Hematol 1994; 46: 304–309.

    Article  CAS  Google Scholar 

  41. Gostissa M, Hofmann TG, Will H, Del Sal G . Regulation of p53 functions: let's meet at the nuclear bodies. Curr Opin Cell Biol 2003; 15: 351–357.

    Article  CAS  Google Scholar 

  42. Hodges M, Tissot C, Howe K, Grimwade D, Freemont PS . Structure, organization, and dynamics of promyelocytic leukemia protein nuclear bodies. Am J Hum Genet 1998; 63: 297–304.

    Article  CAS  Google Scholar 

  43. 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.

    Article  CAS  Google Scholar 

  44. Di Como CJ, Gaiddon C, Prives C . p73 Function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol Cell Biol 1999; 19: 1438–1449.

    Article  CAS  Google Scholar 

  45. Marin MC, Jost CA, Brooks LA, Irwin MS, O'Nions J, Tidy JA et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet 2000; 25: 47–54.

    Article  CAS  Google Scholar 

  46. Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C . A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol 2001; 21: 1874–1887.

    Article  CAS  Google Scholar 

  47. Strano S, Fontemaggi G, Costanzo A, Rizzo MG, Monti O, Baccarini A et al. Physical interaction with human tumor derived p53 mutants inhibits p63 activities. J Biol Chem 2002; 277: 18817–18826.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to William Kaelin Jr, Makoto Hijikata, Massimo Romani and Franco Mandelli for plasmids and helpful suggestions. We thank Sabrina Riccioni for technical assistance. This work has been supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero della Salute-Italy, CNR-Italy, Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) and European Community.

Author information

Authors and Affiliations

  1. Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy

    M G Rizzo, E Giombini, A Sacchi & G Blandino

  2. Department of Cellular Biotechnologies and Hematology, University ‘La Sapienza’, Rome, Italy

    D Diverio & M Vignetti

  3. Laboratory of Hematology and Oncology, Istituto Superiore di Sanità, Rome, Italy

    U Testa

  4. Department of Biopathology, University ‘Tor Vergata’, Rome, Italy

    F Lo-Coco

Authors
  1. M G Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Giombini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Diverio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Vignetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Sacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. U Testa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F Lo-Coco
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G Blandino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M G Rizzo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rizzo, M., Giombini, E., Diverio, D. et al. Analysis of p73 expression pattern in acute myeloid leukemias: lack of ΔN-p73 expression is a frequent feature of acute promyelocytic leukemia. Leukemia 18, 1804–1809 (2004). https://doi.org/10.1038/sj.leu.2403483

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403483

Keywords

This article is cited by

Search

Advanced search

Quick links