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:

The MN1-TEL myeloid leukemia-associated fusion protein has a dominant-negative effect on RAR-RXR-mediated transcription

Oncogene volume 26, pages 5733–5740 (2007)Cite this article

Abstract

The translocation t(12;22)(p13;q11) creates an MN1-TEL fusion gene leading to acute myeloid leukemia. MN1 is a transcription coactivator of the retinoic acid and vitamin D receptors, and TEL (ETV6) is a member of the E26-transformation-specific family of transcription factors. In MN1-TEL, the transactivating domains of MN1 are combined with the DNA-binding domain of TEL. We show that MN1-TEL inhibits retinoic acid receptor (RAR)-mediated transcription, counteracts coactivators such as p160 and p300, and acts as a dominant-negative mutant of MN1. Compared to MN1, the same transactivation domains in MN1-TEL are poorly stimulated by p160, p300 or histone deacetylase inhibitors, indicating that the block of RAR-mediated transcription by MN1-TEL is caused by dysfunctional transactivation domains rather than by recruitment of corepressors. The mechanism leading to myeloid leukemia in t(12;22) thus differs from the translocations that involve RAR itself.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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

  • Bailly RA, Bosselut R, Zucman J, Cormier F, Delattre O, Roussel M et al. (1994). DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma. Mol Cell Biol 14: 3230–3241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beverloo HB, Panagopoulos I, Isaksson M, van Wering E, van Drunen E, de Klein A et al. (2001). Fusion of the Homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Cancer Res 61: 5374–5377.

    CAS  PubMed  Google Scholar 

  • Boer J, Bonten-Surtel J, Grosveld G . (1998). Overexpression of the nucleoporin CAN/NUP214 induces growth arrest, nucleocytoplasmic transport defects, and apoptosis. Mol Cell Biol 18: 1236–1247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bohlander SK . (2005). ETV6: a versatile player in leukemogenesis. Semin Cancer Biol 15: 162–174.

    Article  CAS  PubMed  Google Scholar 

  • Braun BS, Frieden R, Lessnick SL, May WA, Denny CT . (1995). Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis. Mol Cell Biol 15: 4623–4630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buijs A, Sherr S, van Baal S, van Bezouw S, van der Plas D, Geurts Van Kessel A et al. (1995). Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11 [published erratum appears in Oncogene 1995 Aug 17;11(4):809]. Oncogene 10: 1511–1519.

    CAS  PubMed  Google Scholar 

  • Buijs A, van Rompaey L, Molijn AC, Davis JN, Vertegaal AC, Potter MD et al. (2000). The MN1-TEL fusion protein, encoded by the translocation (12;22)(p13;q11) in myeloid leukemia, is a transcription factor with transforming activity. Mol Cell Biol 20: 9281–9293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carella C, Bonten J, Rehg J, Grosveld GC . (2006). MN1-TEL, the product of the t(12;22) in human myeloid leukemia, immortalizes murine myeloid cells and causes myeloid malignancy in mice. Leukemia 20: 1582–1592.

    Article  CAS  PubMed  Google Scholar 

  • Cazzaniga G, Daniotti M, Tosi S, Giudici G, Aloisi A, Pogliani E et al. (2001). The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case. Cancer Res 61: 4666–4670.

    CAS  PubMed  Google Scholar 

  • Chakrabarti SR, Nucifora G . (1999). The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. Biochem Biophys Res Commun 264: 871–877.

    Article  CAS  PubMed  Google Scholar 

  • Goodman RH, Smolik S . (2000). CBP/p300 in cell growth, transformation, and development. Genes Dev 14: 1553–1577.

    CAS  PubMed  Google Scholar 

  • Gossen M, Bujard H . (1992). Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89: 5547–5551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S, Zelent A . (1998). Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91: 2634–2642.

    CAS  PubMed  Google Scholar 

  • Gunther CV, Nye JA, Bryner RS, Graves BJ . (1990). Sequence-specific DNA binding of the proto-oncoprotein ets-1 defines a transcriptional activator sequence within the long terminal repeat of the Moloney murine sarcoma virus. Genes Dev 4: 667–679.

    Article  CAS  PubMed  Google Scholar 

  • Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J et al. (1997). A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression [see comments]. Nature 387: 43–48.

    Article  CAS  PubMed  Google Scholar 

  • Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM et al. (2004). Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. EMBO J 23: 450–459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawagoe H, Grosveld GC . (2005). Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9. Blood 106: 4269–4277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leo C, Chen JD . (2000). The SRC family of nuclear receptor coactivators. Gene 245: 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Meester-Smoor MA, Vermeij M, Van Helmond MJL, Molijn AC, Van Wely KHM, Hekman ACP et al. (2005). Targeted disruption of the Mn1 oncogene results in severe defects in development of membranous bones of the cranial skeleton. Mol Cell Biol 25: 4229–4236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mercader N, Leonardo E, Piedra ME, Martinez AC, Ros MA, Torres M . (2000). Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development 127: 3961–3970.

    CAS  PubMed  Google Scholar 

  • Pattyn F, Speleman F, De Paepe A, Vandesompele J . (2003). RTPrimerDB: the real-time PCR primer and probe database. Nucleic Acids Res 31: 122–123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perissi V, Staszewski LM, McInerney EM, Kurokawa R, Krones A, Rose DW et al. (1999). Molecular determinants of nuclear receptor–corepressor interaction. Genes Dev 13: 3198–3208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sutton AL, Zhang X, Ellison TI, Macdonald PN . (2005). The 1,25(OH)2D3-regulated transcription factor MN1 stimulates vitamin D receptor-mediated transcription and inhibits osteoblastic cell proliferation. Mol Endocrinol 19: 2234–2244.

    Article  CAS  PubMed  Google Scholar 

  • Van Roozendaal KE, Darling D, Farzaneh F . (1990). DMSO and retinoic acid induce HL-60 differentiation by different but converging pathways. Exp Cell Res 190: 137–140.

    Article  CAS  PubMed  Google Scholar 

  • van Wely KH, Molijn AC, Buijs A, Meester-Smoor MA, Aarnoudse AJ, Hellemons A et al. (2003). The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene 22: 699–709.

    Article  CAS  PubMed  Google Scholar 

  • Vivanco Ruiz MM, Bugge TH, Hirschmann P, Stunnenberg HG . (1991). Functional characterization of a natural retinoic acid responsive element. EMBO J 10: 3829–3838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wan YJ, Cai Y, Magee TR . (1998). Retinoic acid differentially regulates retinoic acid receptor-mediated pathways in the Hep3B cell line. Exp Cell Res 238: 241–247.

    Article  CAS  PubMed  Google Scholar 

  • Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C et al. (1998). Role of PML in cell growth and the retinoic acid pathway. Science 279: 1547–1551.

    Article  CAS  PubMed  Google Scholar 

  • Yoshida M, Kijima M, Akita M, Beppu T . (1990). Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265: 17174–17179.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs D Chen and R Eckner for permission to use RAC3 and p300 expression constructs, and E Korpershoek for providing POLR2A primers. This work was supported by Dutch Cancer Society Grants EUR 94-653 and 98-1778 and NCI Grant CA72999. KvW is supported by grant RyC-2004-1886 from the Spanish Ministry of Education and Science.

Author information

Author notes

  1. K H M van Wely

    Present address: 4Current address: Department of Immunology and Oncology, Centro Nacional de Biotecnologia, C. Darwin 3, Madrid, Spain.,

  2. K H M van Wely and M A Meester-Smoor: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, CA, The Netherlands

    K H M van Wely, M A Meester-Smoor, M J F W Janssen, A-J Aarnoudse & E C Zwarthoff

  2. Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA

    G C Grosveld

Authors
  1. K H M van Wely
    View author publications

    Search author on:PubMed Google Scholar

  2. M A Meester-Smoor
    View author publications

    Search author on:PubMed Google Scholar

  3. M J F W Janssen
    View author publications

    Search author on:PubMed Google Scholar

  4. A-J Aarnoudse
    View author publications

    Search author on:PubMed Google Scholar

  5. G C Grosveld
    View author publications

    Search author on:PubMed Google Scholar

  6. E C Zwarthoff
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to E C Zwarthoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Wely, K., Meester-Smoor, M., Janssen, M. et al. The MN1-TEL myeloid leukemia-associated fusion protein has a dominant-negative effect on RAR-RXR-mediated transcription. Oncogene 26, 5733–5740 (2007). https://doi.org/10.1038/sj.onc.1210382

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.onc.1210382

Keywords

This article is cited by

Search

Advanced search

Quick links