{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE315nnn/GSE315409/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Methylation profiling"],"species":["Homo sapiens"],"gds_type":["Methylation profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315409"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"The novel hypomethylating agent NTX-301 reprograms epigenetic and Hippo signaling pathways and exhibits pre-clinical activity in venetoclax-resistant and TP53-mutant AML","description":"Combinations of Hypomethylating agents (HMA) and BCL-2 inhibitor venetoclax (VEN) are frontline therapies for patients with acute myeloid leukemia (AML) with high response rates, but patients ultimately relapse, especially those with TP53 mutations. We investigated therapeutic efficacy and mechanisms of action of NTX-301, a next-generation HMA and demonstrate that NTX-301 is superior to 5-azacytidine (5-AZA), exhibits activities in 5-AZA or VEN-resistant AML and synergizes with VEN in VEN or VEN/HMA resistant and TP53-mutant AML blasts and stem/progenitor cells both, in vitro and in vivo in PDX models. NTX-301 inhibits DNMT1 and increases p73, caspase-8, and activated caspase-8 in TP53-WT and TP53-mutant cells and activates p53 signaling. Methylation profiling analyses revealed that NTX-301 is a more selective hypomethylating agent compared to 5-AZA. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared to 5-AZA-treated cells, and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. Data suggest that NTX-301 displays more potent anti-leukemia activities compared to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML in part by suppressing DNMT1 and inducing DNA damage responses and extrinsic apoptosis and by inducing p53 and demethylating LATS1/2, thus activating Hippo signaling.","dates":{"publication":"2026/06/29"},"accession":"GSE315409","cross_references":{"GSM":["GSM9427146","GSM9427147","GSM9427144","GSM9427145","GSM9427148","GSM9427149","GSM9427150","GSM9427142","GSM9427153","GSM9427143","GSM9427151","GSM9427152"],"GPL":["24676"],"GSE":["315409"],"taxon":["Homo sapiens"]}}