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Chronic Myeloproliferative Neoplasias

BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms

Leukemia volume 28, pages 88–97 (2014)Cite this article

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Abstract

Small molecule inhibition of the BET family of proteins, which bind acetylated lysines within histones, has been shown to have a marked therapeutic benefit in pre-clinical models of mixed lineage leukemia (MLL) fusion protein-driven leukemias. Here, we report that I-BET151, a highly specific BET family bromodomain inhibitor, leads to growth inhibition in a human erythroleukemic (HEL) cell line as well as in erythroid precursors isolated from polycythemia vera patients. One of the genes most highly downregulated by I-BET151 was LMO2, an important oncogenic regulator of hematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon Janus kinase 2 (JAK2) kinase activity in HEL cells. Here, we show that the transcriptional changes induced by a JAK2 inhibitor (TG101209) and I-BET151 in HEL cells are significantly over-lapping, suggesting a common pathway of action. We generated JAK2 inhibitor resistant HEL cells and showed that these retain sensitivity to I-BET151. These data highlight I-BET151 as a potential alternative treatment against myeloproliferative neoplasms driven by constitutively active JAK2 kinase.

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Acknowledgements

We thank members of the Kouzarides laboratory for the thoughtful discussion. The Kouzarides laboratory was supported by Cancer Research UK, Leukaemia and Lymphoma Research, GlaxoSmithKline and BBSRC. Work in the Green laboratory is supported by Leukemia and Lymphoma Research, Cancer Research UK, the Kay Kendall Leukaemia Fund, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, and the Leukemia and Lymphoma Society of America. The Gottgens laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. The Huntly laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. MA Dawson is a Wellcome Trust Beit Fellow and E Cannizzaro and M Wiese are funded by this Fellowship.

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Author notes

  1. B S Wyspiańska, A J Bannister and I Barbieri: These authors contributed equally to this work.

Authors and Affiliations

  1. Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK

    B S Wyspiańska, A J Bannister, I Barbieri, S Robson, M Wiese, E Cannizzaro, M A Dawson & T Kouzarides

  2. Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK

    J Nangalia, A Godfrey, F J Calero-Nieto, J Li, M Wiese, E Cannizzaro, M A Dawson, B Huntly, A R Green & B Gottgens

  3. Department of Haematology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK

    J Nangalia, A Godfrey, J Li, M A Dawson & A R Green

  4. Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK

    I Rioja & R K Prinjha

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  1. B S Wyspiańska
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Correspondence to T Kouzarides.

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Competing interests

T Kouzarides is a founder of Abcam Ltd. RK Prinja and I Rioja are employees and shareholders of GlaxoSmithKline. The remaining authors declare no conflict of interest.

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Wyspiańska, B., Bannister, A., Barbieri, I. et al. BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms. Leukemia 28, 88–97 (2014). https://doi.org/10.1038/leu.2013.234

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