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Transcription linked to recombination: a gene-internal promoter coincides with the recombination hot spot II of the human MLL gene

Oncogene volume 26, pages 1361–1371 (2007)Cite this article

Abstract

The MLL gene is frequently involved in chromosomal translocations associated with high-risk acute leukaemia. Infant and therapy-related acute leukaemia patients display chromosomal breakpoints preferentially clustered in the telomeric portion of the MLL breakpoint cluster region (SCII). Here, we demonstrate that SCII colocalizes with a gene-internal promoter element in the mouse and human MLL gene, respectively. The mRNA generated encodes an N-terminally truncated version of MLL that still exhibits many functional regions, including the C-terminal SET-domain. Etoposide-induced DNA double-strand breaks colocalize with the binding site of RNA polymerase II and the transcription initiation region, but not with a nearby Topo II consensus sequence. Thus, the observed genomic instability of the human MLL gene is presumably linked to transcriptional processes. The consequences of this novel finding for the creation of chromosomal translocations, the biology of the MLL protein and for MLL-mediated acute leukaemia are discussed.

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Acknowledgements

We thank Jay Hess for providing the murine MLL wild-type and knockout fibroblast cell lines, and Tatsuya Nakamura and Eli Canaani (Philadelphia, USA) for providing the polyclonal antiserum PAS173. The MAB E3 was a gift from Robert Slany (Erlangen, Germany). We also thank Michael Karas, Martin Stanulla and Malek Djabali for critically reading the manuscript, and Ludger Klein-Hitpass for performing the Affymetrix experiments. This study was supported by research grants N1KR-S12T13 from the BMBF, Ma1876/5-2 and Ma1876/7-1 from the DFG to R.M.

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Author notes

  1. D Schraets & R Marschalek

    Present address: YES Pharmaceutical Development Services, Bahnstrasse 42-46, D-61381, Friedrichsdorf, Germany

  2. E Pfitzner

    Present address: Institute of Biochemistry and Biophysics, Friedrich-Schiller University Jena, Philosophenweg 12, D-7743, Jena, Germany

  3. S Scharf and J Zech: These authors contributed equally.

Authors and Affiliations

  1. Institute of Pharmaceutical Biology/ZAFES, Biocenter, JWG-University of Frankfurt, Frankfurt/Main, Germany

    S Scharf, J Zech, A Bursen, D Schraets, T Dingermann & R Marschalek

  2. Department of Physiology, Medical Research Council Functional Genetics Unit, Anatomy and Genetics, University of Oxford, Oxford, UK

    P L Oliver

  3. Georg-Speyer-Haus, Frankfurt/Main, Germany

    S Kliem & E Pfitzner

  4. Procompliance Verlag GmbH, Erlangen, Germany

    E Gillert

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Correspondence to R Marschalek.

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Scharf, S., Zech, J., Bursen, A. et al. Transcription linked to recombination: a gene-internal promoter coincides with the recombination hot spot II of the human MLL gene. Oncogene 26, 1361–1371 (2007). https://doi.org/10.1038/sj.onc.1209948

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