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The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

Oncogene volume 35, pages 5272–5281 (2016)Cite this article

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Abstract

C/EBPα (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBPα p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBPα, TRIB2 was unable to induce AML. Only in the presence of C/EBPα p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBPα. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBPα p42 is required for TRIB2-mediated AML.

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Acknowledgements

We thank all the technical staff at the Paul O’Gorman Leukaemia Research Centre. We thank the Cancer Research UK Glasgow Centre (C596/A18076) and the Biological Service Unit facilities at the Cancer Research UK Beatson Institute (C596/A17196) and the Biological Services at the University of Glasgow. We thank Ruaidhrí Carmody for reagents and critical review of the work. We thank the Kay Kendall foundation (KKL501) and the Howat foundation for Flow cytometry facility funding. Work in the Keeshan lab was supported by the Howat Foundation and Children with Cancer UK. CO’C was supported by Childrens Leukaemia Research Project grant. PK was supported by Science Foundation Ireland Infrastructure award and the Mid-Western Cancer Foundation. Work in the Porse lab was supported by a centre grant from the NovoNordisk Foundation (The Novo Nordisk Foundation Section for Stem Cell Biology in Human Disease).

Author contributions

KK designed the study. FL, CO’C, CF, EO, MS and JC performed the research. BP provided transgenic mouse models. BP, PK, RL, RA and MC provided essential reagents and expertise. KK, FL, CO’C, MS, EO and JC analysed the data. CO’C and FL made the figures. KK wrote the paper. All authors edited the paper.

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Authors and Affiliations

  1. Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    C O'Connor, F Lohan, J Campos, M Salomè & K Keeshan

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

    E Ohlsson & B Porse

  3. Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark

    E Ohlsson & B Porse

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

    E Ohlsson & B Porse

  5. University College Cork, Cork, Ireland

    C Forde

  6. School of Chemistry, University of Glasgow, Glasgow, UK

    R Artschwager & R M Liskamp

  7. Department of Haematology, Cork University Hospital, Cork, Ireland

    M R Cahill

  8. Department of Life Sciences, Materials and Surface Science Institute and Stokes Institute, University of Limerick, Limerick, Ireland

    P A Kiely

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Correspondence to K Keeshan.

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O'Connor, C., Lohan, F., Campos, J. et al. The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia. Oncogene 35, 5272–5281 (2016). https://doi.org/10.1038/onc.2016.66

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