{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335569/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Proteomics"],"species":["Mus musculus"],"gds_type":["Protein profiling by protein array"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335569"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Targeting the translation complex eIF4F disrupts BCR::ABL1 tranlstion and overcomes drug resistance in CML","description":"Chronic myeloid leukemia (CML) is driven by the constitutively active BCR::ABL1 kinase, which promotes uncontrolled cell proliferation. While tyrosine kinase inhibitors (TKIs) such as imatinib (IM) have revolutionized CML treatment, resistance, particularly in leukemia stem cells (LSCs), remains a significant barrier to curative therapy. Using a high-content antibody microarray and bioinformatics analyses, we investigated differences in the proteome and phosphorylation landscape of IM-resistant cells and identified highly activated members of the eukaryotic translation initiation complex (eIF4F), particularly eIF4G1, a core component of the eIF4F complex. Notably, these eIF4F complex members are highly expressed and activated in CD34+ CML stem/progenitor cells and in IM-resistant cells. Genetic inhibition of eIF4G1 or pharmacological targeting with the small-molecule inhibitor SBI-756 diminished eIF4F complex assembly, induced an overall reduction in translation initiation of drug-resistant cells, reduced BCR::ABL1 expression, impaired the survival of nonresponder patient stem/progenitor cells, and sensitized them to TKIs, with strong synergistic effects both in vitro and in a PDX model. Molecular and functional validation studies implicated an important role for eIF4G1 in mediating BCR::ABL1 translation initiation and in key downstream targets, including cyclin D3, c-MYC, MCL1, and MDM2, thereby further disrupting the malignant phenotype. These effects were also seen in BCR::ABL1+ acute lymphoblastic leukemia (ALL) cells. These findings underscore the potential of eIF4F complex inhibition, particularly targeting eIF4G1, as a new therapeutic strategy to overcome TKI resistance in CML and other BCR::ABL1+ malignancies.","dates":{"publication":"2026/06/17"},"accession":"GSE335569","cross_references":{"GSM":["GSM9815750","GSM9815761","GSM9815751","GSM9815762","GSM9815760","GSM9815747","GSM9815758","GSM9815748","GSM9815759","GSM9815745","GSM9815756","GSM9815757","GSM9815746","GSM9815754","GSM9815743","GSM9815755","GSM9815744","GSM9815752","GSM9815763","GSM9815741","GSM9815764","GSM9815742","GSM9815753","GSM9815749"],"GPL":["37121"],"GSE":["335569"],"taxon":["Mus musculus"]}}