GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335569/primaryOK200ProteomicsMus musculusProtein profiling by protein arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335569GEOGSEfalseTargeting the translation complex eIF4F disrupts BCR::ABL1 tranlstion and overcomes drug resistance in CMLChronic 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.2026/06/17GSE335569GSM9815750GSM9815761GSM9815751GSM9815762GSM9815760GSM9815747GSM9815758GSM9815748GSM9815759GSM9815745GSM9815756GSM9815757GSM9815746GSM9815754GSM9815743GSM9815755GSM9815744GSM9815752GSM9815763GSM9815741GSM9815764GSM9815742GSM9815753GSM981574937121335569Mus musculus