Targeting the eIF4F translation initiation complex disrupts BCR::ABL1 translation and overcomes drug resistance in...

Chronic myeloid leukemia (CML) is driven by the constitutively active BCR::ABL1 kinase, which promotes uncontrolled cell proliferation. Although protein-tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment, resistance remains a significant barrier to curative therapy, particularly due to BCR::ABL1 mutations and the persistence of leukemia stem cells (LSCs). New treatment strategies that directly inhibit BCR::ABL1 protein expression are needed to achieve more effective therapy. Using a high-content antibody microarray and bioinformatics analyses, we investigated differences in the proteome and phosphorylation landscape of Imatinib (IM)-resistant cells and identified highly activated members of the eukaryotic translation initiation complex (eIF4F), particularly eIF4G1, a core component of eIF4F. 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, reduced overall translation initiation, reduced BCR::ABL1 expression and key downstream targets, impaired the survival of nonresponder stem/progenitor cells, including BCR::ABL1-T315I mutant cells, and sensitized them to TKIs, with strong synergistic effects in vitro and in a PDX model. These findings underscore the potential of eIF4F complex inhibition as a new therapeutic strategy to overcome TKI resistance in CML and other BCR::ABL1⁺ malignancies.