{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324645/"]},"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=GSE324645"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Targeting Y593-phosphorylated DDX5 triggers mitochondrial dysfunction and synergizes with BCL2 inhibition in acute myeloid leukemia","description":"Acute myeloid leukemia (AML) remains a lethal malignancy with limited therapeutic durability. DEAD-box RNA helicase 5 (DDX5) is highly expressed in AML and associated with poor outcome, yet its mechanistic role and therapeutic tractability are incompletely defined. Here, we identify phosphorylation at tyrosine 593 (Y593) of DDX5 as a therapeutic vulnerability in AML. We show that DDX5 is constitutively phosphorylated at Y593 in AML cells independent of Src or c-Abl activity. While genetic depletion of DDX5 suppresses AML growth, phosphorylation-deficient Y593F knock-in mutants show that Y593 phosphorylation is dispensable for baseline proliferation but is required to maintain mitochondrial integrity and define the BCL-2 family–controlled apoptotic threshold. Targeting Y593-phosphorylated DDX5 with the small-molecule RX-5902 destabilizes β-catenin and, more importantly, triggers acute mitochondrial dysfunction characterized by impaired oxidative phosphorylation, permeabilizes mitochondrial outer membranes, and increases BCL-2 dependence. Accordingly, inhibition of Y593-phosphorylated DDX5 represents a mitochondrial sensitizer that creates vulnerability to BCL-2 blockade. Consistent with this mechanism, RX-5902 strongly synergizes with venetoclax across AML cell lines, primary patient samples, and xenograft models. Together, these findings establish Y593-phosphorylated DDX5 as an actionable regulator of mitochondrial apoptotic priming in AML and support combined targeting of DDX5 and BCL-2 as a rational therapeutic strategy.","dates":{"publication":"2026/05/01"},"accession":"GSE324645","cross_references":{"GSM":["GSM9581560","GSM9581551","GSM9581561","GSM9581550","GSM9581553","GSM9581552","GSM9581555","GSM9581554","GSM9581557","GSM9581556","GSM9581559","GSM9581558"],"GPL":["28038"],"GSE":["324645"],"taxon":["Homo sapiens"]}}