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Analysis of 5-Azacytidine Resistance Models Reveals a Set of Targetable Pathways
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SYSNO ASEP 0557510 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Analysis of 5-Azacytidine Resistance Models Reveals a Set of Targetable Pathways Author(s) Minařík, L. (CZ)
Pimková, K. (CZ)
Kokavec, J. (CZ)
Schaffartzikova, A. (CZ)
Vellieux, F. (CZ)
Kulvait, V. (CZ)
Daumová, L. (CZ)
Dusilkova, N. (CZ)
Jonasova, A. (CZ)
Vargova, K. (CZ)
Králová Viziová, Petra (UMG-J)
Sedláček, Radislav (UMG-J) RID
Zemanová, Z. (CZ)
Stopka, T. (CZ)Number of authors 14 Article number 223 Source Title Cells. - : MDPI
Roč. 11, č. 2 (2022)Number of pages 13 s. Publication form Online - E Language eng - English Country CH - Switzerland Keywords myelodysplastic syndrome ; Azacytidine ; resistance ; CDX mice ; pi3k ; AKT signaling Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology R&D Projects LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA19-03586S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000757973600001 DOI 10.3390/cells11020223 Annotation The mechanisms by which myelodysplastic syndrome (MDS) cells resist the effects of hypomethylating agents (HMA) are currently the subject of intensive research. A better understanding of mechanisms by which the MDS cell becomes to tolerate HMA and progresses to acute myeloid leukemia (AML) requires the development of new cellular models. From MDS/AML cell lines we developed a model of 5-azacytidine (AZA) resistance whose stability was validated by a transplantation approach into immunocompromised mice. When investigating mRNA expression and DNA variants of the AZA resistant phenotype we observed deregulation of several cancer-related pathways including the phosphatidylinosito-3 kinase signaling. We have further shown that these pathways can be modulated by specific inhibitors that, while blocking the proliferation of AZA resistant cells, are unable to increase their sensitivity to AZA. Our data reveal a set of molecular mechanisms that can be targeted to expand therapeutic options during progression on AZA therapy. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://www.mdpi.com/2073-4409/11/2/223
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