Analysis of 5-Azacytidine Resistance Models Reveals a Set of Targetable Pathways.
Animals
Azacitidine
/ pharmacology
DNA, Neoplasm
/ genetics
Drug Resistance, Neoplasm
/ drug effects
Mice
Mice, SCID
Models, Biological
Molecular Sequence Annotation
Phosphatidylinositol 3-Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Reproducibility of Results
Signal Transduction
/ drug effects
Transcriptome
/ genetics
Azacytidine
CDX mice
PI3K/AKT signaling
myelodysplastic syndrome
resistance
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
11 01 2022
11 01 2022
Historique:
received:
15
12
2021
revised:
04
01
2022
accepted:
07
01
2022
entrez:
21
1
2022
pubmed:
22
1
2022
medline:
1
3
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35053339
pii: cells11020223
doi: 10.3390/cells11020223
pmc: PMC8774143
pii:
doi:
Substances chimiques
DNA, Neoplasm
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Azacitidine
M801H13NRU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Czech Science Foundation
ID : 19-03586S
Organisme : Ministry of Health
ID : NV19-08-00144, NU21-08-00312, CZ-DRO-VFN64165
Organisme : Charles University
ID : GAUK 1672119, SVV260521, UNCE/MED/016, ProgresQ26
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