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A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

Oncogene volume 29, pages 5796–5808 (2010)Cite this article

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Abstract

The T-cell oncogene Lim-only 2 (LMO2) critically influences both normal and malignant haematopoiesis. LMO2 is not normally expressed in T cells, yet ectopic expression is seen in the majority of T-acute lymphoblastic leukaemia (T-ALL) patients with specific translocations involving LMO2 in only a subset of these patients. Ectopic lmo2 expression in thymocytes of transgenic mice causes T-ALL, and retroviral vector integration into the LMO2 locus was implicated in the development of clonal T-cell disease in patients undergoing gene therapy. Using array-based chromatin immunoprecipitation, we now demonstrate that in contrast to B-acute lymphoblastic leukaemia, human T-ALL samples largely use promoter elements with little influence from distal enhancers. Active LMO2 promoter elements in T-ALL included a previously unrecognized third promoter, which we demonstrate to be active in cell lines, primary T-ALL patients and transgenic mice. The ETS factors ERG and FLI1 previously implicated in lmo2-dependent mouse models of T-ALL bind to the novel LMO2 promoter in human T-ALL samples, while in return LMO2 binds to blood stem/progenitor enhancers in the FLI1 and ERG gene loci. Moreover, LMO2, ERG and FLI1 all regulate the +1 enhancer of HHEX/PRH, which was recently implicated as a key mediator of early progenitor expansion in LMO2-driven T-ALL. Our data therefore suggest that a self-sustaining triad of LMO2/ERG/FLI1 stabilizes the expression of important mediators of the leukaemic phenotype such as HHEX/PRH.

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Acknowledgements

We thank the Kay Kendall Leukaemia Fund, Medical Research Council, Cancer Research UK, National Health and Research Council of Australia, the National Institute for Health Research Cambridge Biomedical Research Centre and Leukaemia and Lymphoma Research UK for grant funding. We are grateful to Michelle Hammet and Tina Hamilton for assistance with pronuclear microinjections and to Professor Sally Kinsey, Leeds Teaching Hospitals, for assistance with sourcing patient material.

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Authors and Affiliations

  1. Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    S H Oram, C Pridans, S J Kinston, S Anand, B J Huntly & B Göttgens

  2. Lowy Cancer Research Centre and The Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia

    J A I Thoms, M E Janes & J E Pimanda

  3. Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada

    J -R Landry

  4. Children's Cancer Institute Australia, University of New South Wales, Sydney, New South Wales, Australia

    R B Lock

  5. Birmingham University Stem Cell Centre, University of Birmingham, Edgbaston, Birmingham, UK

    P -S Jayaraman

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Oram, S., Thoms, J., Pridans, C. et al. A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients. Oncogene 29, 5796–5808 (2010). https://doi.org/10.1038/onc.2010.320

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