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

Andersson, E I
Autor Andersson, E I Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Pützer, S
Autor Pützer, S 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
Yadav, B
Autor Yadav, B Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Dufva, O
Autor Dufva, O Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Khan, S
Autor Khan, S Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
He, L
Autor He, L Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Sellner, L
Autor Sellner, L ORCID Department of Translational Oncology and Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
Schrader, A
Autor Schrader, A 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
Crispatzu, G
Autor Crispatzu, G 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
Oleś, M
Autor Oleś, M Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
Zhang, H
Autor Zhang, H Division of Hematology, Mayo Clinic, Rochester, MN, USA
Adnan-Awad, S
Autor Adnan-Awad, S Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Lagström, S
Autor Lagström, S Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Bellanger, D
Autor Bellanger, D Institut Curie, INSERM U830, PSL Research University, Paris, France
Mpindi, J P
Autor Mpindi, J P Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Eldfors, S
Autor Eldfors, S ORCID Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Pemovska, T
Autor Pemovska, T Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Pietarinen, P
Autor Pietarinen, P Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Lauhio, A
Autor Lauhio, A Department of Medicine, Division of Infectious Disease, Helsinki University Central Hospital (HUCH), Helsinki, Finland
Tomska, K
Autor Tomska, K Department of Translational Oncology and Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
Cuesta-Mateos, C
Autor Cuesta-Mateos, C Departamento de Immunología, Hospital Universitario de la Princesa, Madrid, Spain
Faber, E
Autor Faber, E Department of Hemato-oncology, University Hospital Olomouc, Olomouc, Czech Republic
Koschmieder, S
Autor Koschmieder, S Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Brümmendorf, T H
Autor Brümmendorf, T H Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Kytölä, S
Autor Kytölä, S Helsinki University Central Hospital (HUCH), Laboratory of Genetics, HUSLAB, Helsinki, Finland
Savolainen, E-R
Autor Savolainen, E-R Nordlab Oulu, Hematology Laboratory, MRC Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
Siitonen, T
Autor Siitonen, T Department of Hematology, Oulu University Hospital, MRC Oulu, University of Oulu, Oulu, Finland
Ellonen, P
Autor Ellonen, P Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Kallioniemi, O
Autor Kallioniemi, O ORCID Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Wennerberg, K
Autor Wennerberg, K Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Ding, W
Autor Ding, W Division of Hematology, Mayo Clinic, Rochester, MN, USA
Stern, M-H
Autor Stern, M-H Institut Curie, INSERM U830, PSL Research University, Paris, France
Huber, W
Autor Huber, W ORCID Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
Anders, S
Autor Anders, S ORCID Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Tang, J
Autor Tang, J Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland Department of Mathematics and Statistics, University of Turku, Turku, Finland
Aittokallio, T
Autor Aittokallio, T Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland Department of Mathematics and Statistics, University of Turku, Turku, Finland
Zenz, T
Autor Zenz, T Department of Translational Oncology and Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
Herling, M
Autor Herling, M 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
Mustjoki, S
Autor Mustjoki, S Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

Leukemia. 2018 Mar ; 32 (3) : 774-787. [epub] 20170814

ISSN 1476-5551 | 0887-6924
Zdroj

Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz https://www.medvik.cz/link/pmid28804127

PubMed 28804127
DOI 10.1038/leu.2017.252
PII: leu2017252
Knihovny.cz E-zdroje

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.

Departamento de Immunología Hospital Universitario de la Princesa Madrid Spain

Department 1 of Internal Medicine Center for Integrated Oncology CMMC Center for Molecular Medicine University of Cologne Germany

Department of Hemato oncology University Hospital Olomouc Olomouc Czech Republic

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

Department of Hematology Oulu University Hospital MRC Oulu University of Oulu Oulu Finland

Department of Mathematics and Statistics University of Turku Turku Finland

Department of Medicine 5 University Hospital Heidelberg Heidelberg Germany

Department of Medicine Division of Infectious Disease Helsinki University Central Hospital Helsinki Finland

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

Division of Hematology Mayo Clinic Rochester MN USA

Genome Biology Unit European Molecular Biology Laboratory Heidelberg Germany

Helsinki University Central Hospital Laboratory of Genetics HUSLAB Helsinki Finland