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Acute Leukemias

TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia

Leukemia volume 29, pages 1018–1031 (2015)Cite this article

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Abstract

Members of the TALE (three-amino-acid loop extension) family of atypical homeodomain-containing transcription factors are important downstream effectors of oncogenic fusion proteins involving the mixed lineage leukemia (MLL) gene. A well-characterized member of this protein family is MEIS1, which orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). TGIF1/TGIF2 are relatively uncharacterized TALE transcription factors, which, in contrast to the remaining family, have been shown to act as transcriptional repressors. Given the general importance of this family in malignant hematopoiesis, we therefore tested the potential function of TGIF1 in the maintenance of MLL-rearranged AML. Gene expression analysis of MLL-rearranged patient blasts demonstrated reduced TGIF1 levels, and, in accordance, we find that forced expression of TGIF1 in MLL-AF9-transformed cells promoted differentiation and cell cycle exit in vitro, and delayed leukemic onset in vivo. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating with MEIS1-bound regions in a competitive manner and that the MEIS1:TGIF1 ratio influence the clinical outcome. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for leukemic maintenance and provide novel insights into the regulatory gene expression circuitries in MLL-rearranged AML.

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Acknowledgements

This study was supported by the Danish Research Council for Medical Research and through a center grant from the NovoNordisk Foundation (The Novo Nordisk Foundation Section for Stem Cell Biology in Human Disease). We thank Anna Fossum for help with cell sorting.

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Authors and Affiliations

  1. The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark,

    A Willer, J S Jakobsen, E Ohlsson, N Rapin, J Waage & B T Porse

  2. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

    A Willer, J S Jakobsen, E Ohlsson, N Rapin, J Waage & B T Porse

  3. Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark,

    A Willer, J S Jakobsen, E Ohlsson, N Rapin, J Waage & B T Porse

  4. Department of Biology, The Bioinformatic Centre, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark,

    N Rapin & J Waage

  5. Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund, Sweden

    M Billing & S Karlsson

  6. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    L Bullinger

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  1. A Willer
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Willer, A., Jakobsen, J., Ohlsson, E. et al. TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia. Leukemia 29, 1018–1031 (2015). https://doi.org/10.1038/leu.2014.307

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