{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE296nnn/GSE296895/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE296895"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Targeting PRMT9 Overcomes Venetoclax Resistance In AML By Modulation Splicing And Inhibiting Translation","description":"Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is critical for promoting acute myeloid leukemia (AML) growth. But its role in BCL2 inhibitor venetoclax resistance (VEN-R) remains elusive. Here, through a loss-of-function screen in VEN-R primary AML patient-derived xenograft (PDX) cells and cell lines, we identified PRMT9 as a critical regulator to promote VEN resistance. Among PRMTs, PRMT9 is preferentially overexpressed in VEN-R AML cell lines and samples, and its inhibition re-sensitized the cells to VEN treatment. We further report synergy of a PRMT9 inhibitor LD2 with VEN in eradicating resistant AML in preclinical models. Mechanistically, PRMT9 ablation in VEN-R cells disrupted RNA splicing by inducing exon skipping of key regulators such as ALG13, eventually leading to downregulation of ATP-binding transporter encoded by ABCC1 responsible for VEN efflux. Concurrently, PRMT9 inhibition suppressed protein translation, resulting in the degradation of short-lived oncoproteins, including MCL1. These findings establish a critical role for PRMT9-mediated arginine methylation in promoting VEN-R and highlight the potency of combining PRMT9 inhibition with VEN as a novel therapeutic strategy against AML.","dates":{"publication":"2026/05/11"},"accession":"GSE296895","cross_references":{"GSM":["GSM8979560","GSM8979563","GSM8979562","GSM8979561"],"GPL":["34281"],"GSE":["296895"],"taxon":["Homo sapiens"]}}