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 Article
  • Published:

ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia

Oncogene volume 33, pages 5501–5510 (2014)Cite this article

Subjects

Abstract

Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. Here, we demonstrate that ZRF1 depletion decreases cell proliferation, induces apoptosis and enhances cell differentiation in human AML cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genome-wide expression study reveals that ZRF1 regulates the transcription of nearly half of RA target genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis, and differentiation, ZRF1 depletion strongly inhibits leukemia progression in a xenograft mouse model. Finally, ZRF1 knockdown cooperates with RA treatment in leukemia suppression in vivo. Taken together, our data reveal that ZRF1 is a key transcriptional regulator in leukemia progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML treatment.

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

Similar content being viewed by others

References

  1. Nowak D, Stewart D, Koeffler HP . Differentiation therapy of leukemia: 3 decades of development. Blood 2009; 113: 3655–3665.

    Article  CAS  Google Scholar 

  2. Deschler B, Lubbert M . Acute myeloid leukemia: epidemiology and etiology. Cancer 2006; 107: 2099–2107.

    Article  Google Scholar 

  3. Tenen DG . Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer 2003; 3: 89–101.

    Article  CAS  Google Scholar 

  4. Uribesalgo I, Di Croce L . Dynamics of epigenetic modifications in leukemia. Brief Funct Genomics 2011; 10: 18–29.

    Article  CAS  Google Scholar 

  5. Wang ZY, Chen Z . Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111: 2505–2515.

    Article  CAS  Google Scholar 

  6. Duester G . Retinoic acid synthesis and signaling during early organogenesis. Cell 2008; 134: 921–931.

    Article  CAS  Google Scholar 

  7. Chanda B, Ditadi A, Iscove NN, Keller G . Retinoic Acid signaling is essential for embryonic hematopoietic stem cell development. Cell 2013; 155: 215–227.

    Article  CAS  Google Scholar 

  8. Friedman AD . Transcriptional control of granulocyte and monocyte development. Oncogene 2007; 26: 6816–6828.

    Article  CAS  Google Scholar 

  9. Tang XH, Gudas LJ . Retinoids retinoic acid receptors, and cancer. Annu Rev Pathol 2011; 6: 345–364.

    Article  CAS  Google Scholar 

  10. Altucci L, Gronemeyer H . The promise of retinoids to fight against cancer. Nat Rev Cancer 2001; 1: 181–193.

    Article  CAS  Google Scholar 

  11. Richly H, Rocha-Viegas L, Ribeiro JD, Demajo S, Gundem G, Lopez-Bigas N et al. Transcriptional activation of polycomb-repressed genes by ZRF1. Nature 2010; 468: 1124–1128.

    Article  CAS  Google Scholar 

  12. Ribeiro JD, Morey L, Mas A, Gutierrez A, Luis NM, Mejetta S et al. ZRF1 controls oncogene-induced senescence through the INK4-ARF locus. Oncogene 2013; 32: 2161–2168.

    Article  CAS  Google Scholar 

  13. Greiner J, Ringhoffer M, Taniguchi M, Hauser T, Schmitt A, Dohner H et al. Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia. Int J Cancer 2003; 106: 224–231.

    Article  CAS  Google Scholar 

  14. Greiner J, Ringhoffer M, Taniguchi M, Li L, Schmitt A, Shiku H et al. mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. Int J Cancer 2004; 108: 704–711.

    Article  CAS  Google Scholar 

  15. Siegel S, Wirth S, Schweizer M, Schmitz N, Zeis M . M-phase phosphoprotein 11 is a highly immunogenic tumor antigen in patients with acute myeloid leukemia. Acta Haematol 2012; 127: 193–197.

    Article  Google Scholar 

  16. Schmitt M, Li L, Giannopoulos K, Chen J, Brunner C, Barth T et al. Chronic myeloid leukemia cells express tumor-associated antigens eliciting specific CD8+ T-cell responses and are lacking costimulatory molecules. Exp Hematol 2006; 34: 1709–1719.

    Article  CAS  Google Scholar 

  17. Giannopoulos K, Li L, Bojarska-Junak A, Rolinski J, Dmoszynska A, Hus I et al. Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia. Int J Oncol 2006; 29: 95–103.

    CAS  Google Scholar 

  18. Resto VA, Caballero OL, Buta MR, Westra WH, Wu L, Westendorf JM et al. A putative oncogenic role for MPP11 in head and neck squamous cell cancer. Cancer Res 2000; 60: 5529–5535.

    CAS  PubMed  Google Scholar 

  19. Dermime S, Grignani F, Rogaia D, Liberatore C, Marchesi E, Gambacorti-Passerini C . Acute promyelocytic leukaemia cells resistant to retinoic acid show further perturbation of the RAR alpha signal transduction system. Leuk Lymphoma 1995; 16: 289–295.

    Article  CAS  Google Scholar 

  20. Oren T, Sher JA, Evans T . Hematopoiesis and retinoids: development and disease. Leuk Lymphoma 2003; 44: 1881–1891.

    Article  CAS  Google Scholar 

  21. Lehmann S, Paul C, Torma H . Retinoid receptor expression and its correlation to retinoid sensitivity in non-M3 acute myeloid leukemia blast cells. Clin Cancer Res 2001; 7: 367–373.

    CAS  PubMed  Google Scholar 

  22. Campos EI, Reinberg D . Histones: annotating chromatin. Annu Rev Genet 2009; 43: 559–599.

    Article  CAS  Google Scholar 

  23. Uckun FM . Severe combined immunodeficient mouse models of human leukemia. Blood 1996; 88: 1135–1146.

    CAS  PubMed  Google Scholar 

  24. Kastner P, Chan S . Function of RARalpha during the maturation of neutrophils. Oncogene 2001; 20: 7178–7185.

    Article  CAS  Google Scholar 

  25. Smith JC, Duchesne MA, Tozzi P, Ethier M, Figeys D . A differential phosphoproteomic analysis of retinoic acid-treated P19 cells. J Proteome Res 2007; 6: 3174–3186.

    Article  CAS  Google Scholar 

  26. Uribesalgo I, Buschbeck M, Gutierrez A, Teichmann S, Demajo S, Kuebler B et al. E-box-independent regulation of transcription and differentiation by MYC. Nat Cell Biol 2011; 13: 1443–1449.

    Article  CAS  Google Scholar 

  27. Minucci S, Nervi C, Lo Coco F, Pelicci PG . Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias? Oncogene 2001; 20: 3110–3115.

    Article  CAS  Google Scholar 

  28. Jaiswal H, Conz C, Otto H, Wolfle T, Fitzke E, Mayer MP et al. The chaperone network connected to human ribosome-associated complex. Mol Cell Biol 2011; 31: 1160–1173.

    Article  CAS  Google Scholar 

  29. Shoji W, Inoue T, Yamamoto T, Obinata M . MIDA1a, protein associated with Id, regulates cell growth. J Biol Chem 1995; 270: 24818–24825.

    Article  CAS  Google Scholar 

  30. Anguille S, Van Tendeloo VF, Berneman ZN . Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia. Leukemia 2012; 26: 2186–2196.

    Article  CAS  Google Scholar 

  31. Zuber J, Rappaport AR, Luo W, Wang E, Chen C, Vaseva AV et al. An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes Dev 2011; 25: 1628–1640.

    Article  CAS  Google Scholar 

  32. Villa R, Pasini D, Gutierrez A, Morey L, Occhionorelli M, Vire E et al. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. Cancer cell 2007; 11: 513–525.

    Article  CAS  Google Scholar 

  33. Huang da W, Sherman BT, Lempicki RA . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009; 37: 1–13.

    Article  Google Scholar 

  34. Frith MC, Fu Y, Yu L, Chen JF, Hansen U, Weng Z . Detection of functional DNA motifs via statistical over-representation. Nucleic Acids Res 2004; 32: 1372–1381.

    Article  CAS  Google Scholar 

  35. Jolma A, Yan J, Whitington T, Toivonen J, Nitta KR, Rastas P et al. DNA-binding specificities of human transcription factors. Cell 2013; 152: 327–339.

    Article  CAS  Google Scholar 

  36. Berge T, Matre V, Brendeford EM, Saether T, Luscher B, Gabrielsen OS . Revisiting a selection of target genes for the hematopoietic transcription factor c-Myb using chromatin immunoprecipitation and c-Myb knockdown. Blood Cells Mol Dis 2007; 39: 278–286.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the members of the LDC laboratory for discussions, the CRG Genomic Unit, and VA Raker for help in preparing the manuscript. This work was supported by grants from the Spanish ‘Ministerio de Educación y Ciencia’ (BFU2010-18692), from AGAUR, from ‘Fundació La Marató’ and from by European Commission’s 7th Framework Program 4DCellFate grant number 277899 to LDC; SD was supported by a PFIS fellowship of the ‘Instituto de Salud Carlos III’.

Author information

Authors and Affiliations

  1. Centre de Regulació Genòmica (CRG), Barcelona, Spain

    S Demajo, I Uribesalgo, A Gutiérrez, C Ballaré & L Di Croce

  2. UPF, Barcelona, Spain

    S Demajo, I Uribesalgo, A Gutiérrez, C Ballaré & L Di Croce

  3. Unidad de Animal de Laboratorio, PRBB, Barcelona, Spain

    S Capdevila & J Martín-Caballero

  4. Institute of Molecular Pathology (IMP), Vienna, Austria

    M Roth & J Zuber

  5. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    L Di Croce

Authors
  1. S Demajo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Uribesalgo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Gutiérrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Ballaré
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Capdevila
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Zuber
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Martín-Caballero
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Di Croce
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Di Croce.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Demajo, S., Uribesalgo, I., Gutiérrez, A. et al. ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia. Oncogene 33, 5501–5510 (2014). https://doi.org/10.1038/onc.2013.501

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.501

Keywords

This article is cited by

Search

Advanced search

Quick links