期刊
EUROPEAN JOURNAL OF HAEMATOLOGY
卷 104, 期 2, 页码 125-137出版社
WILEY
DOI: 10.1111/ejh.13354
关键词
cell death; myelodysplastic syndromes (MDS); PLK1; secondary acute myeloid leukemia (sAML); volasertib
类别
资金
- Hans-und-Klementia-Langmatz-Stiftung
- Deutsche Jose Carreras Leukamie-Stiftung/DGHO
- DGHO/GMIHO
- Deutsche Jose Carreras LeukamieStiftung [DJCLS R 14/16, DJCLS R 12/22, DJCLS 21R/2016]
- German Research Foundation [FOR 2033, Go 713/2-1, SFB 1243]
- Deutsche Konsortium fur translationale Krebsforschung (DKTK) of the German Cancer Center (DKFZ)
- Max Eder-Program grant from the Deutsche Krebshilfe [111738]
- Else Kroner Fresenius Stiftung [2014_A185]
- Boehringer Ingelheim RCV GmbH Co KG
- Deutsche Forschungsgemeinschaft [DFG FOR 2036]
Introduction 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. Objectives 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. Methods Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 mu M 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. Results 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. Conclusions 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.
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