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Alteration of N6-Methyladenosine mRNAMethylation in an hiPSC-CMs Model of TKI-induced cardiotoxicity

ABSTRACT: Alteration of N6-Methyladenosine mRNAMethylation in an hiPSC-CMs Model of TKI-induced cardiotoxicity

PROVIDER: PRJNA793785 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17408300_1.fastq.gz	Fastqsanger.gz
	SRR17408300_2.fastq.gz	Fastqsanger.gz
	SRR17408301_1.fastq.gz	Fastqsanger.gz
	SRR17408301_2.fastq.gz	Fastqsanger.gz
	SRR17408302_1.fastq.gz	Fastqsanger.gz

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Project description:Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for explore the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a practical approach for using donor-specific iPSC-CMs to predict personalized doxorubicin (DOX)-induced cardiotoxicity (DIC) prior to chemotherapy. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice, and largely replicated the reported mechanisms of DIC. By categorizing iPSC-CMs into DOX-resistant and DOX-sensitive cell lines based on their phenotypic reactions to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we assessed the limitations of the model for identification of potential genetic/molecular biomarker and pinpointed a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. We also discussed the selection of DOX dose and exposure duration for inter-individual variability of DIC assessment. Our results support the utility of donor-specific iPSC-CMs in assessing inter-individual difference and enabling personalized cardiotoxicity prediction. Further studies will encompass a large panel of donor-specific iPSC-CMs to investigate the role of the DND1 and known DIC genetic variants, and to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.

Dataset Information

Alteration of N6-Methyladenosine mRNAMethylation in an hiPSC-CMs Model of TKI-induced cardiotoxicity

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