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A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology

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Abstract

MLL-AF4 fusion is the most common consequence of chromosomal translocations in infant leukaemia and is associated with a poor prognosis. MLL-AF4 is thought to be required in haematopoietic stem cells to elicit leukaemia and may be involved in tumour phenotype specification as it is only found in B-cell tumours in humans. We have employed the invertor conditional technology to create a model of MLL-AF4, in which a floxed AF4 cDNA was knocked into Mll in the opposite orientation for transcription. Cell-specific Cre expression was used to generate Mll-AF4 expression. The mice develop exclusively B-cell lineage neoplasias, whether the Cre gene was controlled by B- or T-cell promoters, but of a more mature phenotype than normally observed in childhood leukaemia. These findings show that the MLL-AF4 fusion protein does not have a mandatory role in multi-potent haematopoietic stem cells to cause cancer and indicates that MLL-AF4 has an instructive function in the phenotype of the tumour.

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Acknowledgements

This work was funded by the Medical Research Council. M Metzler is the recipient of a fellowship from the German Research Foundation, and MN Lobato was the recipient of a Kay Kendall fellowship. MJ Arends is supported by Cancer Research United Kingdom. We also thank A Middleton, G King, C Peace, C Rickett and R Berks for animal husbandary and A Lenton for the illustration work. We thank Cordelia Langford for help and advice during the microarray analysis.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    M Metzler, A Forster, R Pannell, A Daser, M N Lobato & T H Rabbitts

  2. Department of Pathology, University of Cambridge, Cambridge, UK

    M J Arends

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  1. M Metzler
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  2. A Forster
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  3. R Pannell
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  4. M J Arends
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  5. A Daser
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  6. M N Lobato
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  7. T H Rabbitts
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Corresponding author

Correspondence to T H Rabbitts.

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

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Metzler, M., Forster, A., Pannell, R. et al. A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology. Oncogene 25, 3093–3103 (2006). https://doi.org/10.1038/sj.onc.1209636

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  • DOI: https://doi.org/10.1038/sj.onc.1209636

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