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Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

Oncogene volume 25, pages 4840–4847 (2006)Cite this article

Abstract

The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1α–aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein. Functional studies show that TEL-ARNT interacts with HIF1α and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1α/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34+ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.

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Acknowledgements

This work was partly supported by INSERM, Association Contre le Cancer (ARC), Fondation pour la Recherche Médicale (FRM), Ligue Nationale Contre le Cancer (LNCC), Comité national and Comité de Paris (JG and OAB are équipes labellisées LNCC). We thank D Brugnon and P Puech for skillful help in FACS analyses, A Yoshimura for the Myc tag, A Kung for discussion, M Vekemans for help in improving the manuscript and R Berger for constant support.

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Authors and Affiliations

  1. Service d'hématologie biologique, Groupe hospitalier Pitié-Salpêtrière, Paris, France

    F Nguyen-Khac

  2. E0210 INSERM, IRNEM, Université Paris V, Hôpital Necker, Paris, France

    F Nguyen-Khac, V Della Valle & O A Bernard

  3. Institut Curie, CNRS UMR146, Orsay, France

    R G Lopez & J Ghysdael

  4. Département d'hématologie, INSERM U567, CNRS UMR 8104, Institut Cochin, Paris, France

    E Ravet & S Fichelson

  5. INSERM U674, Paris, France

    M Mauchauffé

  6. Division of Pediatric Oncology, Johns Hopkins Oncology Center, Baltimore, MD, USA

    A D Friedman

  7. Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, MD, USA

    L E Huang

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  1. F Nguyen-Khac
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  2. V Della Valle
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Correspondence to F Nguyen-Khac.

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

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Nguyen-Khac, F., Della Valle, V., Lopez, R. et al. Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation. Oncogene 25, 4840–4847 (2006). https://doi.org/10.1038/sj.onc.1209503

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