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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 [OPEN ACCESS]
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Jost Philipp

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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)
secondary acute myeloid leukemia (sAML)
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