{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE349nnn/GSE349089/"]},"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=GSE349089"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML by Inhibiting Drp1-Dependent Mitochondrial Fission and Destabilizing Mcl-1 [scRNA-Seq 2]","description":"ERK1/2-mediated phosphorylation of Drp1 drives mitochondrial fission, stemness, and therapy resistance in RAS-driven solid tumors; however, its role in acute myeloid leukemia (AML) remains unclear. We identified ERK1/2-mediated Drp1 phosphorylation as a mechanism of resistance to venetoclax in AML. ERK1/2 inhibition using Compound 27 (ERKi), an analog of the clinical ERK1/2 inhibitor ASTX029, reduced mitochondrial fission, induced ROS accumulation, mitochondrial depolarization, and apoptosis in venetoclax-resistant AML cells. ERKi sensitized resistant AML cells to venetoclax and depleted leukemia progenitor cells in primary AML samples. Conversely, overexpression of Drp1-phosphomimetic restored mitochondrial fission and reversed apoptosis induced by venetoclax alone and in combination with ERKi. In post-venetoclax/decitabine relapsed human AML PDX model, co-treatment with venetoclax and ASTX029 improved survival and reduced leukemia burden accompanied by decreased pDrp1-Ser616, Mcl-1, and pMcl-1-Thr163 expression in bone marrow-derived human leukemic cells. In conclusion, inhibiting the ERK1/2-Drp1 axis overcomes resistance to venetoclax in AML.","dates":{"publication":"2026/09/30"},"accession":"GSE349089","cross_references":{"GSM":["GSM10086956","GSM10086957","GSM10086954","GSM10086955","GSM10086952","GSM10086953"],"GPL":["28038"],"GSE":["349089"],"taxon":["Homo sapiens"]}}