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Molecular targets for therapy

Reinstated p53 response and high anti-T-cell leukemia activity by the novel alkylating deacetylase inhibitor tinostamustine

Leukemia volume 34, pages 2513–2518 (2020)Cite this article

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A Correction to this article was published on 23 October 2020

This article has been updated

T-cell prolymphocytic leukemia (T-PLL) is the most frequent mature T-cell leukemia in Western countries. Its inherently aggressive growth and a notoriously chemotherapy refractory behavior result in overall survival times of <20–36 months [1, 2]. There are no formally licensed drugs for T-PLL. Although the anti-CD52 monoclonal antibody alemtuzumab induces high primary response rates, the vast majority of patients relapse on average within 12 months thereafter [3, 4]. Presentation at a median age of 63 years and post-induction conditions render 50–70% of patients ineligible for allogeneic stem cell transplantation. Moreover, long-term disease control can only be accomplished for a proportion of 20–30% of transplanted patients. Overall, T-PLL remains an insufficiently addressed rare entity with urgently needed novel treatment designs.

The molecular and diagnostic hallmarks of T-PLL are the chromosomal aberrations inv(14), t(14;14), and t(X;14), which underlie constitutive expression of the proto-oncogenes T-cell leukemia/lymphoma 1A (TCL1A) or Mature T-cell Proliferation 1 (MTCP1). The oncogenic role of both of these TCL1-family genes was proven in Lck-hTCL1A [5] and CD2-hMTCP1 [6] transgenic (tg) mice. They develop T-cell expansions that closely resemble human T-PLL. TCL1A acts as a coactivator of pro-survival AKT [2].

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Fig. 1: Principle of (H)DAC inhibition combined with DNA damage induction in a single agent reinstates p53 activation and reduces T-PLL cell survival.
Fig. 2: Anti-leukemic efficacy of EDO-S101 in vivo.

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  • 23 October 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

MH is funded by the German Research Foundation (DFG) as part of the collaborative “CONTROL-T” research consortium on mature T-cell lymphomas (FOR1961; HE3553/4-2). Further support to MH: CECAD, CMMC, German José Carreras Leukemia Foundation (DJCLS; R12/08), Fritz Thyssen foundation (10.15.2.034MN), and the DFG KFO-286 (HE-3553/3-2). AS is funded by a scholarship through the DJCLS (03F/2016). AS and MH receive joint support by the DFG (SCHR1668/1-1). TB is funded by the Köln Fortune Program. The European Union supports MH as part of the Transcan-II initiative (ERANET-PLL) as well as MH, SM, and TA as part of EraPerMed JAKSTAT-TARGET. TA is funded by Academy of Finland (grants 279163, 310507, 326238), Cancer Society of Finland (TA). SM is supported by ERC CoG grant (M-IMM), Academy of Finland and Finnish Cancer Organizations. EDO-S101 and research support were provided by Mundipharma EDO GmbH. Open access funding provided by Projekt DEAL.

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Author notes

  1. These authors contributed equally: A. Schrader, M. Herling

Authors and Affiliations

  1. Department of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), University of Cologne (UoC), Cologne, Germany

    S. Pützer, L. Varghese, J. von Jan, T. Braun, P. Mayer, N. Riet, S. Oberbeck, A. Schrader & M. Herling

  2. Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), UoC, Cologne, Germany

    S. Pützer, L. Varghese, J. von Jan, T. Braun, P. Mayer, S. Oberbeck, A. Schrader & M. Herling

  3. Center for Molecular Medicine Cologne (CMMC), UoC, Cologne, Germany

    S. Pützer, L. Varghese, J. von Jan, T. Braun, P. Mayer, N. Riet, S. Oberbeck, A. Schrader & M. Herling

  4. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    A. K. Giri, S. Timonen, H. Kuusanmäki & T. Aittokallio

  5. Translational Immunology Research Program, University of Helsinki, Helsinki, Finland

    S. Timonen, H. Kuusanmäki & S. Mustjoki

  6. Hematology Research Unit Helsinki, Helsinki University Hospital, Comprehensive Cancer Center, Helsinki, Finland

    S. Timonen, H. Kuusanmäki & S. Mustjoki

  7. Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland

    S. Timonen, H. Kuusanmäki & S. Mustjoki

  8. INSERM U830, Institut Curie, PSL Research University, Paris, 75013, France

    M.-H. Stern

  9. Department of Mathematics and Statistics, University of Turku, Turku, Finland

    T. Aittokallio

  10. Senckenberg Institute of Pathology, Goethe-University, Frankfurt am Main, Germany

    S. Newrzela

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  1. S. Pützer
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Contributions

Design and experimental data analysis: MH, AS, SP; experiments: SP, AS, LV, PM, NR, JJ, TB, ST, SO, SN, SM, HK; biostatistics: AK, TA; patient samples: MH, M-HS; manuscript preparation: SP, AS, and MH.

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Correspondence to M. Herling.

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Pützer, S., Varghese, L., von Jan, J. et al. Reinstated p53 response and high anti-T-cell leukemia activity by the novel alkylating deacetylase inhibitor tinostamustine. Leukemia 34, 2513–2518 (2020). https://doi.org/10.1038/s41375-020-0772-6

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