Analysis of 5-Azacytidine Resistance Models Reveals a Set of Targetable Pathways

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...

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Published in:Cells (Basel, Switzerland) Switzerland), 2022-01, Vol.11 (2), p.223
Main Authors: Minařík, Lubomír, Pimková, Kristýna, Kokavec, Juraj, Schaffartziková, Adéla, Vellieux, Fréderic, Kulvait, Vojtěch, Daumová, Lenka, Dusilková, Nina, Jonášová, Anna, Vargová, Karina Savvulidi, Králová Viziová, Petra, Sedláček, Radislav, Zemanová, Zuzana, Stopka, Tomáš
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Animals
Azacitidine - pharmacology
Azacytidine
CDX mice
Cell culture
Cell growth
Cell proliferation
Cloning
DNA methylation
DNA, Neoplasm - genetics
Drug dosages
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Gene expression
Genomes
Kinases
Leukemia
Mice
Mice, SCID
Models, Biological
Molecular modelling
Molecular Sequence Annotation
Myelodysplastic syndrome
Patients
Phenotypes
Phosphatidylinositol 3-Kinases - metabolism
PI3K/AKT signaling
Proto-Oncogene Proteins c-akt - metabolism
Reproducibility of Results
resistance
Signal Transduction - drug effects
Transcriptome - genetics
Transplantation
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Summary: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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11020223