Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Hatzl, S; Perfler, B; Wurm, S; Uhl, B; Quehenberger, F; Ebner, S; Troppmair, J; Reinisch, A; Wölfler, A; Sill, H; Zebisch, A.
Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia.
Cancers (Basel). 2020; 12(2):
Doi: 10.3390/cancers12020496
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- Führende Autor*innen der Med Uni Graz
- Hatzl Stefan
- Zebisch Armin
- Co-Autor*innen der Med Uni Graz
- Perfler Bianca
- Quehenberger Franz
- Reinisch Andreas
- Sill Heinz
- Uhl Barbara
- Wölfler Albert
- Wurm Sonja
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- Abstract:
- Resistance to chemotherapy is one of the primary obstacles in acute myeloid leukemia (AML) therapy. Micro-RNA-23a (miR-23a) is frequently deregulated in AML and has been linked to chemoresistance in solid cancers. We, therefore, studied its role in chemoresistance to cytarabine (AraC), which forms the backbone of all cytostatic AML treatments. Initially, we assessed AraC sensitivity in three AML cell lines following miR-23a overexpression/knockdown using MTT-cell viability and soft-agar colony-formation assays. Overexpression of miR-23a decreased the sensitivity to AraC, whereas its knockdown had the opposite effect. Analysis of clinical data revealed that high miR-23a expression correlated with relapsed/refractory (R/R) AML disease stages, the leukemic stem cell compartment, as well as with inferior overall survival (OS) and event-free survival (EFS) in AraC-treated patients. Mechanistically, we demonstrate that miR-23a targets and downregulates topoisomerase-2-beta (TOP2B), and that TOP2B knockdown mediates AraC chemoresistance as well. Likewise, low TOP2B expression also correlated with R/R-AML disease stages and inferior EFS/OS. In conclusion, we show that increased expression of miR-23a mediates chemoresistance to AraC in AML and that it correlates with an inferior outcome in AraC-treated AML patients. We further demonstrate that miR-23a causes the downregulation of TOP2B, which is likely to mediate its effects on AraC sensitivity.
- Find related publications in this database (Keywords)
- micro-RNA-23a
- acute myeloid leukemia
- therapeutic resistance
- cytarabine