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Ectopic expression of the HLXB9 gene is associated with an altered nuclear position in t(7;12) leukaemias

Leukemia volume 23, pages 1179–1182 (2009)Cite this article

From our findings and earlier reports,2 it is apparent that a position effect mechanism triggers the expression of HLXB9 in the t(7;12) leukaemias. However, this is the first study that correlates aberrant gene expression with altered gene positioning as a consequence of a specific chromosomal translocation. In this case, the radial nuclear position of HLXB9 is altered after juxtaposition to an actively transcribed region. The ETV6 gene, that is expressed ubiquitously, is normally localized in the inner portion of the nucleus (see Figure 3). On the other hand, HLXB9, that is not transcriptionally active after the developmental stages of embryonic life, is normally localized toward the nuclear periphery.8 We have shown here that the translocated HLXB9 locus is brought to a more internal position by its translocation partner ETV6 in t(7;12) leukaemic cells, in which the HLXB9 expression is activated.

The chromosome region that includes ETV6 is shown to be an active gene-rich area, suggesting that at least some of these genes may be upregulated by positive cis elements. This might mean that the juxtaposition of the HLXB9 gene to the downstream region of the ETV6 gene causes an ectopic interaction between active cis elements (known to be capable of acting over large distances) and the HLXB9 promoter, both derepressing and upregulating its transcription. Activation of the HLXB9 expression through cis elements could occur soon after breakage and reunion of the DNA filaments, with concurrent repositioning of the chromatin at the nuclear level. This would render certain areas of the genome more exposed to the transcription machinery, resulting in a stable overexpression of HLXB9. Further work will focus on the study of epigenetic modifications occurring in these translocation cases. This will aim to support the circumstantial evidence provided here for a position effect mechanism, and will also provide mechanistic information to complement our observations on nuclear positioning and gene expression.

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Acknowledgements

This work was supported in part by the Leukaemia Research Fund UK (EB and ST). The authors would like to thank Dr Joanna Bridger, CCCB, Brunel University, for valuable comments and critical reading of this manuscript.

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Author notes

  1. E Ballabio and C D Cantarella: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biosciences, Centre for Cell and Chromosome Biology and Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, West London, UK

    E Ballabio & S Tosi

  2. Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK

    E Ballabio

  3. Department of Animal Biology ‘M. La Greca’, University of Catania, Catania, Italy

    C D Cantarella, C Federico, P Di Mare & S Saccone

  4. Department of Paediatrics, University of Catania, Catania, Italy

    P Di Mare

  5. Paediatric Haematology/Oncology Unit, Oxford Children's Hospital, John Radcliffe Hospital, Oxford, UK

    G Hall

  6. Department of Pediatric Hematology and Oncology, Oncogenetic Laboratory, Justus-Liebig University, Giessen, Germany

    J Harbott

  7. MRC Department of Molecular Haematology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    J Hughes

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  1. E Ballabio
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Correspondence to S Tosi.

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Ballabio, E., Cantarella, C., Federico, C. et al. Ectopic expression of the HLXB9 gene is associated with an altered nuclear position in t(7;12) leukaemias. Leukemia 23, 1179–1182 (2009). https://doi.org/10.1038/leu.2009.15

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