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 Paper
  • Published:

Molecular signature of retinoic acid treatment in acute promyelocytic leukemia

Oncogene volume 24, pages 3358–3368 (2005)Cite this article

Abstract

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a block of differentiation at the promyelocytic stage. APL patients respond to pharmacological concentrations of all-trans retinoic acid (RA) and disease remission correlates with terminal differentiation of leukemic blasts. The PML/RAR oncogenic transcription factor is responsible for both the pathogenesis of APL and for its sensitivity to RA. In order to identify physiological targets of RA therapy, we analysed gene expression profiles of RA-treated APL blasts and found 1056 common target genes. Comparing these results to those obtained in RA-treated U937 cell lines revealed that transcriptional response to RA is largely dependent on the expression of PML/RAR. Several genes involved in the control of differentiation and stem cell renewal are early targets of RA regulation, and may be important effectors of RA response. Modulation of chromatin modifying genes was also observed, suggesting that specific structural changes in local chromatin domains may be required to promote RA-mediated differentiation. Computational analysis of upstream genomic regions in RA target genes revealed nonrandom distribution of transcription factor binding sites, indicating that specific transcriptional regulatory complexes may be involved in determining RA response.

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
Figure 5
Figure 6

Similar content being viewed by others

References

  • Alberta JA, Springett GM, Rayburn H, Natoli TA, Loring J, Kreidberg JA and Housman D . (2003). Blood, 101, 2570–2574.

  • Alcalay M, Meani N, Gelmetti V, Fantozzi A, Fagioli M, Orleth A, Riganelli D, Sebastiani C, Cappelli E, Casciari C, Sciurpi MT, Mariano AR, Minardi SP, Luzi L, Muller H, Di Fiore PP, Frosina G and Pelicci PG . (2003). J. Clin. Invest., 112, 1751–1761.

  • Alcalay M, Orleth A, Sebastiani C, Meani N, Chiaradonna F, Casciari C, Sciurpi MT, Gelmetti V, Riganelli D, Minucci S, Fagioli M and Pelicci PG . (2001). Oncogene, 20, 5680–5694.

  • Benedetti L, Grignani F, Scicchitano BM, Jetten AM, Diverio D, Lo Coco F, Avvisati G, Gambacorti-Passerini C, Adamo S, Levin AA, Pelicci PG and Nervi C . (1996). Blood, 87, 1939–1950.

  • Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S and Pelicci PG . (2002). Science, 295, 1079–1082.

  • Fazi F, Travaglini L, Carotti D, Palitti F, Diverio D, Alcalay M, McNamara S, Miller WH, Lo Coco F, Pelicci PG and Nervi C . (2005). Ongogene, in press.

  • Finocchiaro G, Parise P, Minardi SP, Alcalay M and Muller H . (2004). Bioinformatics, 20, 3670–3672.

  • Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Lazar MA, Minucci S and Pelicci PG . (1998). Nature, 391, 815–818.

  • Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, Mencarelli A, Grignani F, Peschle C, Nicoletti I and Pelicci PG . (1993). Cell, 74, 423–431.

  • Guo Y, Chan R, Ramsey H, Li W, Xie X, Shelley WC, Martinez-Barbera JP, Bort B, Zaret K, Yoder M and Hromas R . (2003). Blood, 102, 2428–2435.

  • He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A and Pandolfi PP . (1998). Nat. Genet., 18, 126–135.

  • Hollander M and Wolfe D . (1999). Nonparametric Statistical Methods, 2nd edn. Wiley: New York.

    Google Scholar 

  • Hosack DA, Dennis Jr G, Sherman BT, Lane HC and Lempicki RA . (2003). Genome Biol., 4, R70.

  • Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ and Wang ZY . (1988). Blood, 72, 567–572.

  • Kamashev D, Vitoux D and De The H . (2004). J. Exp. Med., 199, 1163–1174.

  • Kel AE, Kel-Margoulis OV, Farnham PJ, Bartley SM, Wingender E and Zhang MQ . (2001). J. Mol. Biol., 309, 99–120.

  • Lacaud G, Gore L, Kennedy M, Kouskoff V, Kingsley P, Hogan C, Carlsson L, Speck N, Palis J and Keller G . (2002). Blood, 100, 458–466.

  • Lee KH, Chang MY, Ahn JI, Yu DH, Jung SS, Choi JH, Noh YH, Lee YS and Ahn MJ . (2002). Biochem. Biophys. Res. Commun., 296, 1125–1133.

  • Leone G, Voso MT, Teofili L and Lubbert M . (2003). Clin. Immunol., 109, 89–102.

  • Lin RJ, Egan DA and Evans RM . (1999). Trends Genet., 15, 179–184.

  • Liu TX, Zhang JW, Tao J, Zhang RB, Zhang QH, Zhao CJ, Tong JH, Lanotte M, Waxman S, Chen SJ, Mao M, Hu GX, Zhu L and Chen Z . (2000). Blood, 96, 1496–1504.

  • Lo Coco F, Diverio D, Pandolfi PP, Biondi A, Rossi V, Avvisati G, Rambaldi A, Arcese W, Petti MC, Meloni G, Mandelli F, Grignani F, Masera G, Barbui T and Pelicci PG . (1992). Lancet, 340, 1437–1438.

  • Meng G, Inazawa J, Ishida R, Tokura K, Nakahara K, Aoki K and Kasai M . (2000). Gene, 242, 59–64.

  • Minucci S and Pelicci PG . (1999). Semin. Cell Dev. Biol., 10, 215–225.

  • Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, Sargin B, Kohler G, Stelljes M, Puccetti E, Ruthardt M, deVos S, Hiebert SW, Koeffler HP, Berdel WE and Serve H . (2004). Mol. Cell Biol., 24, 2890–2904.

  • Ohneda O, Ohneda K, Arai F, Lee J, Miyamoto T, Fukushima Y, Dowbenko D, Lasky LA and Suda T . (2001). Blood, 98, 2134–2142.

  • Park DJ, Vuong PT, de Vos S, Douer D and Koeffler HP . (2003). Blood, 102, 3727–3736.

  • Quandt K, Frech K, Karas H, Wingender E and Werner T . (1995). Nucleic Acids Res., 23, 4878–4884.

  • Radtke F, Wilson A, Ernst B and MacDonald HR . (2002). Immunol. Rev., 187, 65–74.

  • Segalla S, Rinaldi L, Kilstrup-Nielsen C, Badaracco G, Minucci S, Pelicci PG and Landsberger N . (2003). Mol. Cell. Biol., 23, 8795–8808.

  • Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H and Shinkai Y . (2002). Genes Dev., 16, 1779–1791.

  • Tamayo P, Slonim D, Mesirov J, Zhu Q, Kitareewan S, Dmitrovsky E, Lander ES and Golub TR . (1999). Proc. Natl. Acad. Sci. USA, 96, 2907–2912.

  • Vernell R, Helin K and Muller H . (2003). J. Biol. Chem., 278, 46124–46137.

  • Wang J and Yen A . (2004). Mol. Cell. Biol., 24, 2423–2443.

  • Wang LC, Swat W, Fujiwara Y, Davidson L, Visvader J, Kuo F, Alt FW, Gilliland DG, Golub TR and Orkin SH . (1998). Genes Dev., 12, 2392–2402.

  • Witcher M, Ross DT, Rousseau C, Deluca L and Miller Jr WH . (2003). Blood, 102, 237–245.

  • Zheng X, Beissert T, Kukoc-Zivojnov N, Puccetti E, Altschmied J, Strolz C, Boehrer S, Gul H, Schneider O, Ottmann OG, Hoelzer D, Henschler R and Ruthardt M . (2004). Blood, 103, 3535–3543.

Download references

Acknowledgements

We are grateful to Roberta Bergomas, Elisa Venturini and Laura Tizzoni for excellent technical support and to Elisabetta Citterio and Lucilla Luzi for helpful discussions. This work was supported by grants from AIRC (Associazione Italiana per la Ricerca sul Cancro) to M Alcalay and PG Pelicci. N Meani and S Licciulli were supported by fellowships from Fondazione Italiana per la Ricerca sul Cancro.

Author information

Authors and Affiliations

  1. IFOM – Institute of Molecular Oncology of the Italian Foundation for Cancer Research, Via Adamello 16, 20139, Milan, Italy

    Natalia Meani, Simone Minardi, Silvia Licciulli, Pier Giuseppe Pelicci, Heiko Müller & Myriam Alcalay

  2. European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy

    Natalia Meani, Silvia Licciulli, Pier Giuseppe Pelicci, Heiko Müller & Myriam Alcalay

  3. San Raffaele Bio-medical Science Park of Rome, Via di Castel Romano 100, 00128, Rome, Italy

    Vania Gelmetti & Clara Nervi

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

    Francesco Lo Coco

Authors
  1. Natalia Meani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simone Minardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Licciulli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vania Gelmetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Lo Coco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Clara Nervi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pier Giuseppe Pelicci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heiko Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Myriam Alcalay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Myriam Alcalay.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meani, N., Minardi, S., Licciulli, S. et al. Molecular signature of retinoic acid treatment in acute promyelocytic leukemia. Oncogene 24, 3358–3368 (2005). https://doi.org/10.1038/sj.onc.1208498

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208498

Keywords

This article is cited by

Search

Advanced search

Quick links