Resistance of Leukemia Cells to 5-Azacytidine: Different Responses to the Same Induction Protocol

Šimoničová, Kristína; Janotka, Ľuboš; Kavcová, Helena; Sulová, Zdena; Messingerová, Lucia; Breier, Albert

doi:10.3390/cancers15113063

Cited by 2 publications

(2 citation statements)

References 49 publications

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“…To further characterize the RIPK3 epigenetic regulation, we used a pharmacological treatment of cell lines using 5-Aza-2 ′ deoxycytidine (Aza), an FDA-and EMA-approved medication for certain leukemias [39]. Aza is a cytidine analog and an inhibitor of DNA methyltransferases that induces passive demethylation with progressive replication [40].…”

Section: Discussionmentioning

confidence: 99%

Biomarker RIPK3 Is Silenced by Hypermethylation in Melanoma and Epigenetic Editing Reestablishes Its Tumor Suppressor Function

Arroyo Villora,

Castellanos Silva,

Zenz

et al. 2024

Genes

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For several decades, cancers have demonstrably been one of the most frequent causes of death worldwide. In addition to genetic causes, cancer can also be caused by epigenetic gene modifications. Frequently, tumor suppressor genes are epigenetically inactivated due to hypermethylation of their CpG islands, actively contributing to tumorigenesis. Since CpG islands are usually localized near promoters, hypermethylation of the promoter can have a major impact on gene expression. In this study, the potential tumor suppressor gene Receptor Interacting Serine/Threonine Protein Kinase 3 (RIPK3) was examined for an epigenetic regulation and its gene inactivation in melanomas. A hypermethylation of the RIPK3 CpG island was detected by bisulfite pyrosequencing and was accompanied by a correlated loss of its expression. In addition, an increasing RIPK3 methylation rate was observed with increasing tumor stage of melanomas. For further epigenetic characterization of RIPK3, epigenetic modulation was performed using a modified CRISPR/dCas9 (CRISPRa activation) system targeting its DNA hypermethylation. We observed a reduced fitness of melanoma cells by (re-)expression and demethylation of the RIPK3 gene using the epigenetic editing-based method. The tumor suppressive function of RIPK3 was evident by phenotypic determination using fluorescence microscopy, flow cytometry and wound healing assay. Our data highlight the function of RIPK3 as an epigenetically regulated tumor suppressor in melanoma, allowing it to be classified as a biomarker.

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Section: Discussionmentioning

confidence: 99%

Biomarker RIPK3 Is Silenced by Hypermethylation in Melanoma and Epigenetic Editing Reestablishes Its Tumor Suppressor Function

Arroyo Villora,

Castellanos Silva,

Zenz

et al. 2024

Genes

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“…However, azacitidine chemotherapy is not always effective due to the drug resistance, which threatens patient survival. Numerous studies have attempted to uncover the mechanisms of azacitidine resistance in AML [ 3 , 4 , 5 , 6 ]. Sripayap et al [ 3 ] generated two azacitidine-resistant cell lines and uncovered genetic disparities between the resistant cell lines.…”

Section: Introductionmentioning

confidence: 99%

Differential Gene Regulatory Network Analysis between Azacitidine-Sensitive and -Resistant Cell Lines

Park,

Miyano

2024

IJMS

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Azacitidine, a DNA methylation inhibitor, is employed for the treatment of acute myeloid leukemia (AML). However, drug resistance remains a major challenge for effective azacitidine chemotherapy, though several studies have attempted to uncover the mechanisms of azacitidine resistance. With the aim to identify the mechanisms underlying acquired azacitidine resistance in cancer cell lines, we developed a computational strategy that can identify differentially regulated gene networks between drug-sensitive and -resistant cell lines by extending the existing method, differentially coexpressed gene sets (DiffCoEx). The technique specifically focuses on cell line-specific gene network analysis. We applied our method to gene networks specific to azacitidine sensitivity and identified differentially regulated gene networks between azacitidine-sensitive and -resistant cell lines. The molecular interplay between the metallothionein gene family, C19orf33, ELF3, GRB7, IL18, NRN1, and RBM47 were identified as differentially regulated gene network in drug resistant cell lines. The biological mechanisms associated with azacitidine and AML for the markers in the identified networks were verified through the literature. Our results suggest that controlling the identified genes (e.g., the metallothionein gene family) and “cellular response”-related pathways (“cellular response to zinc ion”, “cellular response to copper ion”, and “cellular response to cadmium ion”, where the enriched functional-related genes are MT2A, MT1F, MT1G, and MT1E) may provide crucial clues to address azacitidine resistance in patients with AML. We expect that our strategy will be a useful tool to uncover patient-specific molecular interplay that provides crucial clues for precision medicine in not only gastric cancer but also complex diseases.

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Resistance of Leukemia Cells to 5-Azacytidine: Different Responses to the Same Induction Protocol

Cited by 2 publications

References 49 publications

Biomarker RIPK3 Is Silenced by Hypermethylation in Melanoma and Epigenetic Editing Reestablishes Its Tumor Suppressor Function

Biomarker RIPK3 Is Silenced by Hypermethylation in Melanoma and Epigenetic Editing Reestablishes Its Tumor Suppressor Function

Differential Gene Regulatory Network Analysis between Azacitidine-Sensitive and -Resistant Cell Lines

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