Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Mayer, M.
miR-23a mediates resistance to hypomethylating agents in myeloid neoplasms
Humanmedizin; [ Diplomarbeit ] Medizinische Universität Graz; 2021. pp. 30
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Hatzl Stefan
- Zebisch Armin
- Altmetrics:
- Abstract:
- Background and Aim Resistance to chemotherapy is one of the major problems in the therapy of myeloid neoplasms (MNs). In AML, aberrant micro-RNA-23a (miR-23a) expression has already been described to be of functional importance in leukemia development. In a prior project our group has shown that increased expression of miR-23a mediates resistance to cytarabine in AML (Hatzl S et al., Cancers 2020). Another therapeutic concept is non-intensive AML therapy with hypomethylating agents (HMAs), with azacitidine being the most commonly employed HMA. Here, we studied whether miR-23a expression also mediates resistance to HMAs in myeloid leukemias. Materials and Methods Lentiviral miR-23a overexpression and shRNA-mediated miR-23a knockdown was performed in myeloid THP-1 and U937 cells. miR-23a expression was assessed by quantitative-real-time PCR (qPCR). For chemosensitivity assays, cells were incubated with azacitidine for 48h. Subsequently, we analyzed the effects on inducing apoptosis in AnnexinV/7-AAD assays, and on cell viability in MTT assays. To delineate the clinical relevance, miR-23a expression of seven sequential primary patient samples of MDS/CMML and AML was measured by qPCR. These samples were obtained from peripheral blood or bone marrow before and after HMA treatment. Results Functional experiments after miR-23a overexpression and miR-23a knockdown, respectively, showed that miR-23a is indeed involved in developing azacitidine resistance. While the azacitidine-induced apoptosis could be increased by miR-23a knockdown, it was decreased by overexpression of this miR. In the analysis of patient specimens, we detected increased miR-23a expression in therapeutic stages of azacitidine resistance. Conclusion miR-23a mediates resistance to HMAs in MDS/CMML and AML. As resistance to cytarabine has also been demonstrated, these data underline the importance of finding new approaches in therapy for MN patients with increased miR-23a expression.