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TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

Oncogene volume 26, pages 4404–4414 (2007)Cite this article

Abstract

The t(12;21)(p13;q22) translocation generates the TEL-AML1 (TEL, translocation-Ets-leukemia; AML1, acute myeloid leukemia-1) (ETV6-RUNX1) fusion product and is the most common chromosomal abnormality in pediatric leukemia. Our previous studies using a murine fetal liver transplantation model demonstrated that TEL-AML1 promotes the self-renewal of B-cell precursors in vitro and enhances the expansion of hematopoietic stem cells (HSCs) in vivo. This is consistent with the hypothesis that TEL-AML1 induces expansion of a preleukemic clone. Several studies have described domains within TEL-AML1 involved in the transcriptional regulation of specific target genes. However, it is unclear which of these domains is important for the activity of TEL-AML1 in preleukemic hematopoiesis. In order to examine this, we have generated a panel of deletion mutants and expressed them in HSCs. These experiments demonstrate that TEL-AML1 requires multiple domains from both TEL and AML1 to alter hematopoiesis. Furthermore, mutation of a single amino-acid residue within the runt homology domain of AML1, required for DNA binding, was sufficient to abrogate TEL-AML1 activity. These data suggest that TEL-AML1 acts as an aberrant transcription factor to perturb multiple pathways during hematopoiesis.

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Acknowledgements

We thank Sarah Horton, Rebecca Randall and Jasper de Boer (Institute of Child Health) for their help and support, Nancy Speck and Matthew Cheney (Dartmouth Medical School) for their advice on AML1 point mutations and Ewan Cameron (University of Glasgow Veterinary School) and Shai Izraeli (Sheba Medical Center) for useful discussions about our work. This work was supported by funding from the Leukaemia Research Fund and Children With Leukaemia, UK.

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  1. Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, UK

    M Morrow, A Samanta, H J M Brady & O Williams

  2. Division of Molecular Immunology, National Institute for Medical Research, London, UK

    D Kioussis

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  1. M Morrow
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Correspondence to O Williams.

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

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Morrow, M., Samanta, A., Kioussis, D. et al. TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL. Oncogene 26, 4404–4414 (2007). https://doi.org/10.1038/sj.onc.1210227

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