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Epigenetic targeting of Notch1-driven transcription using the HDACi panobinostat is a potential therapy against T-cell acute lymphoblastic leukemia

Leukemia volume 32, pages 237–241 (2018)Cite this article

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T-cell acute lymphoblastic leukemia (T-ALL) is a disease characterized by the uncontrolled clonal proliferation of immature lymphoid cells. Despite improvement in remission rates using conventional chemotherapeutics, the prognosis for T-ALL remains poor due to disease relapse associated with intrinsic, or acquired tumor cell resistance to the initial therapies.1 Thus, there is a clear need to design novel therapeutic approaches that can target molecular pathways and cellular processes important for T-ALL proliferation and survival. Although T-ALL is a genetically heterogeneous disease, mutations resulting in activation of the Notch-1 signaling pathway are present in over 50% of patients, thus defining Notch signaling as a central player in T-ALL onset and progression.2 Gene expression analysis has demonstrated that the gene signatures of Notch-driven primary human T-ALL, human cell lines and Notch-driven mouse T-ALL models are remarkably similar, validating the use of murine T-ALL models induced by exogenous Notch.3 These studies also defined an oncogenic c-MYC gene signature as a key characteristic of these T-ALL and connectivity map (C-Map) experiments implicated histone deacetylase inhibitors (HDACi) as potential modifiers of pathways de-regulated by Notch.3 In line with this, it has been recently proposed that the BET bromodomain BRD4 inhibitor JQ1 was effective against Notch-1 driven T-ALL by indirect targeting of c-Myc and its associated downstream transcriptional program.4

HDACi are a class of compounds capable of inducing large-scale epigenetic changes via deacetylation of both histone and non-histone proteins.5 HDACi are FDA approved for the treatment of cutaneous T-cell lymphoma,6 and have proved effective in a wide range of murine models of hematological malignancies.7 Importantly, panobinostat, an FDA-approved HDACi shows efficacy against human T-ALL cell lines in vitro.3, 8 A poorly understood effect of HDACi treatment is repression of Myc expression and its oncogenic function. HDACi have been suggested to cause downregulation of Myc expression in a wide range of tumor types9 as well as reactivation of genes transcriptionally repressed by Myc.10

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Acknowledgements

The work was funded by the Australian National Health and Medical Research Council. MW was supported by a fellowship from the Deutsche Forschungsgemeinschaft and funding from the NHMRC. SJV was funded by a Rubicon fellowship from the Netherlands Organization for Scientific Research. EDH was supported by a fellowship from the National Health and Medical Research Council of Australia. RWJ was supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship, project and program grants from the NHMRC, the Cancer Council Victoria and the Victorian Cancer Agency. EDH would like to thank Sarah Russell for mentorship through the project.

Author contributions

MW, SJV, SH, EDH and RWJ designed the experiments. MW, SJV, IYK, BPM, KMR and EDH performed the experiments. MW, SJV, IYK, BPM, KMR and EDH analyzed the data. MW, SJV, EDH and RWJ wrote the manuscript.

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Author notes

  1. M Waibel, S J Vervoort, E D Hawkins and R W Johnstone: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Therapeutics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    M Waibel, S J Vervoort, B P Martin & R W Johnstone

  2. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    M Waibel, S J Vervoort, K M Ramsbottom & R W Johnstone

  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia

    M Waibel, S J Vervoort & R W Johnstone

  4. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

    I Y Kong, S Heinzel & E D Hawkins

  5. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia

    I Y Kong, S Heinzel & E D Hawkins

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  1. M Waibel
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Corresponding authors

Correspondence to E D Hawkins or R W Johnstone.

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Competing interests

The Johnstone laboratory receives research funding from Novartis for studies involving panobinostat.

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Waibel, M., Vervoort, S., Kong, I. et al. Epigenetic targeting of Notch1-driven transcription using the HDACi panobinostat is a potential therapy against T-cell acute lymphoblastic leukemia. Leukemia 32, 237–241 (2018). https://doi.org/10.1038/leu.2017.282

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