{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE309nnn/GSE309897/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"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=GSE309897"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Manipulation of Mitochondrial Metabolism Sensitizes AML to MCL-1 Inhibition","description":"MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes such as those harboring KMT2A rearrangements (KMT2A-r). Clinical trials of MCL-1 inhibitors have been limited by modest efficacy and dose-limiting toxicity, underscoring the need for rational combination strategies. Here, we identify inhibition of electron transport chain complex I (CI) as a synthetic lethal partner for MCL-1 blockade. Mechanistically, CI suppression activates the mitochondrial stress arm of the integrated stress response (ISR), sensitizing leukemia cells to apoptosis upon MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML.","dates":{"publication":"2026/06/23"},"accession":"GSE309897","cross_references":{"GSM":["GSM9284619","GSM9284625","GSM9284614","GSM9284624","GSM9284613","GSM9284612","GSM9284623","GSM9284622","GSM9284618","GSM9284629","GSM9284628","GSM9284617","GSM9284616","GSM9284627","GSM9284615","GSM9284626","GSM9284621","GSM9284620"],"GPL":["24676"],"GSE":["309897"],"taxon":["Homo sapiens"],"PMID":["[42350371]"]}}