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Molecular targets for therapy

Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling

Leukemia volume 32, pages 774–787 (2018)Cite this article

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Abstract

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase–signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

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Acknowledgements

This work was supported by the Academy of Finland, the Finnish Cancer Societies, Finnish Cancer Institute, Instrumentarium Science Foundation, Biomedicum Helsinki Foundation, Sigrid Juselius Foundation, European Regional Development Fund, Signe and Ane Gyllenberg Foundation, Swedish Cultural Foundation, Blood Disease Foundation the Finnish Cultural Foundation. MH and AS were supported by the DFG Research Unit FOR1961 (CONTROL-T; HE3553/4-2), by the Köln Fortune program by the Fritz Thyssen Foundation (10.15.2.034MN) and by the José Carreras Leukemia Foundation (DJCLS 03F/2016). TA and JT were supported by European Union’s Horizon 2020 research and innovation program (grant Agreement No. 634143, MedBioinformatics). MO, WH and TZ were supported by the European Commission’s Horizon 2020 Project SOUND. We thank Professor Kimmo Porkka and Dr Caroline Heckman for their scientific input; Dr Esa Jantunen, Dr Marja Pyörälä, Dr Marjut Kauppila, Dr Maija Itälä-Remes and Dr Veli Kairisto for providing patient information and the personnel at the Hematology Research Unit Helsinki and FIMM for their expert clinical and technical assistance.

Author contributions

EIA and SM designed the study, coordinated the project, analyzed the data and wrote the paper. EIA and SL performed sequence analysis and validated mutations. EIA, SP, OD, TP and PP designed and performed the functional experiments. BY, SAK, LH, SE, GC, MO and JPM designed and performed the bioinformatics analysis. LS, AS, SP, HZ, DB, AL, KT, CC-M, EF, SK, ERS, TS and TB provided patient samples and participated in the laboratory studies. SA, PE, OK, WD, M-HS, WH, KW, JT, TA, TZ and MH participated in the study design, data analysis and contributed to write the paper. All authors read and approved the final manuscript.

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Author notes

  1. T Pemovska

    Present address: 17Current address: CEMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.,

Authors and Affiliations

  1. Department of Clinical Chemistry and Hematology, Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

    E I Andersson, B Yadav, O Dufva, S Adnan-Awad, P Pietarinen & S Mustjoki

  2. Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), CMMC, Center for Molecular Medicine, University of Cologne, Germany,

    S Pützer, A Schrader, G Crispatzu & M Herling

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

    B Yadav, S Khan, L He, S Lagström, J P Mpindi, S Eldfors, T Pemovska, P Ellonen, O Kallioniemi, K Wennerberg, S Anders, J Tang & T Aittokallio

  4. Department of Translational Oncology and Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany

    L Sellner, K Tomska & T Zenz

  5. Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany

    L Sellner, K Tomska & T Zenz

  6. Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

    M Oleś & W Huber

  7. Division of Hematology, Mayo Clinic, Rochester, MN, USA,

    H Zhang & W Ding

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

    D Bellanger & M-H Stern

  9. Department of Medicine, Division of Infectious Disease, Helsinki University Central Hospital (HUCH), Helsinki, Finland

    A Lauhio

  10. Departamento de Immunología, Hospital Universitario de la Princesa, Madrid, Spain

    C Cuesta-Mateos

  11. Department of Hemato-oncology, University Hospital Olomouc, Olomouc, Czech Republic

    E Faber

  12. Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    S Koschmieder & T H Brümmendorf

  13. Helsinki University Central Hospital (HUCH), Laboratory of Genetics, HUSLAB, Helsinki, Finland

    S Kytölä

  14. Nordlab Oulu, Hematology Laboratory, MRC Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland

    E-R Savolainen

  15. Department of Hematology, Oulu University Hospital, MRC Oulu, University of Oulu, Oulu, Finland

    T Siitonen

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

    J Tang & T Aittokallio

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  1. E I Andersson
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Correspondence to S Mustjoki.

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Competing interests

Labcyte, Inc. and FIMM/University of Helsinki have a collaboration agreement on the utilization of Labcyte’s acoustic dispensing technologies. CC-M is an employee of IMMED.S.L. SM has received honoraria and research funding from Novartis, Pfizer and Bristol-Myers Squibb (not related to this study). KW has received honoraria and research funding from Novartis and Pfizer (not related to this study). The other authors declare no conflict of interest.

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Andersson, E., Pützer, S., Yadav, B. et al. Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling. Leukemia 32, 774–787 (2018). https://doi.org/10.1038/leu.2017.252

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