Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Dill, V; Kauschinger, J; Hauch, RT; Buschhorn, L; Odinius, TO; Müller-Thomas, C; Mishra, R; Kyncl, MC; Schmidt, B; Prodinger, PM; Hempel, D; Bellos, F; Höllein, A; Kern, W; Haferlach, T; Slotta-Huspenina, J; Bassermann, F; Peschel, C; Götze, KS; Waizenegger, IC; Höckendorf, U; Jost, PJ; Jilg, S.
Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis.
Eur J Haematol. 2020; 104(2):125-137
Doi: 10.1111/ejh.13354
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- Co-Autor*innen der Med Uni Graz
- Jost Philipp
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- Abstract:
- Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections. The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect. Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 μM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry. Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status. Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment. © 2019 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Aged -
- Aged, 80 and over -
- Bone Marrow Cells - metabolism
- Bone Marrow Cells - pathology
- Cell Cycle Proteins - antagonists & inhibitors
- Cell Cycle Proteins - metabolism
- Female -
- Gene Expression Regulation, Leukemic - drug effects
- Hematopoiesis - drug effects
- Humans -
- Leukemia, Myeloid, Acute - drug therapy
- Leukemia, Myeloid, Acute - metabolism
- Leukemia, Myeloid, Acute - pathology
- Male -
- Myelodysplastic Syndromes - drug therapy
- Myelodysplastic Syndromes - metabolism
- Myelodysplastic Syndromes - pathology
- Myeloid Cell Leukemia Sequence 1 Protein - biosynthesis
- Protein-Serine-Threonine Kinases - antagonists & inhibitors
- Protein-Serine-Threonine Kinases - metabolism
- Proto-Oncogene Proteins - antagonists & inhibitors
- Proto-Oncogene Proteins - metabolism
- Pteridines - administration & dosage
- Pteridines - adverse effects
- Receptor-Interacting Protein Serine-Threonine Kinases - biosynthesis
- Find related publications in this database (Keywords)
- cell death
- myelodysplastic syndromes (MDS)
- PLK1
- secondary acute myeloid leukemia (sAML)
- volasertib