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Acute lymphoblastic leukemia

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

Leukemia volume 31, pages 2037–2047 (2017)Cite this article

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Abstract

Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.

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Acknowledgements

We thank the following funding agencies: Fund for Scientific Research Flanders (‘FWO Vlaanderen’ research projects GA00113N, 3G065614, G.0C47.13N and 31500615W to PVV; research projects G.0529.12N and G.0817.13N to GB; doctoral grant to SP; postdoctoral grant to SG; BP is a senior clinical investigator), Children Cancer Fund Ghent, Belgian Foundation Against Cancer (Grants 365W3415W and B/13590) and the Belgian Stand Up To Cancer Foundation (Research Grant 365Y9115W; doctoral grant to SP; postdoctoral grants to TP and FM), agency for Innovation by Science and Technology (‘IWT’, SB Grant 111528 to NV), Geconcerteerde Onderzoeksacties Ghent University (GOA-01GB1013W to GB), Cancer League of the Canton of Zurich, Empiris Foundation, Kinderkrebsforschung Schweiz, Sassella Foundation, Stiftung für Krebsbekämpfung, Swiss National Science Foundation (310030-133108), Fondation Panacée and the clinical research focus program ‘Human Hemato-Lymphatic Diseases’ of the University of Zurich. We also thank Lindy Reunes for excellent technical assistance and the Innovative Flemish in vivo imaging technology (INFINITY) laboratory at Ghent University Hospital. Finally, the computational resources (Stevin Supercomputer Infrastructure) and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by Ghent University, the Hercules Foundation and the Flemish Government–Department EWI.

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  1. S Peirs and V Frismantas: These authors contributed equally to this work.

  2. J-P Bourquin and P Van Vlierberghe: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Medical Genetics, Ghent University, Ghent, Belgium

    S Peirs, F Matthijssens, W Van Loocke, T Pieters, B Lintermans, B Poppe, S Goossens & P Van Vlierberghe

  2. Cancer Research Institute Ghent (CRIG), Ghent, Belgium

    S Peirs, F Matthijssens, W Van Loocke, T Pieters, N Vandamme, B Lintermans, G Berx, B Poppe, S Goossens & P Van Vlierberghe

  3. Department of Pediatric Oncology, Children’s Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland

    V Frismantas, B C Bornhauser & J-P Bourquin

  4. Molecular and Cellular Oncology Lab, VIB Inflammation Research Center, Ghent University, Ghent, Belgium

    T Pieters, N Vandamme, G Berx & S Goossens

  5. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    T Pieters, N Vandamme, G Berx & S Goossens

  6. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

    M P Dobay

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Peirs, S., Frismantas, V., Matthijssens, F. et al. Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia. Leukemia 31, 2037–2047 (2017). https://doi.org/10.1038/leu.2017.10

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