Targeting the translation complex eIF4F disrupts BCR::ABL1 tranlstion and overcomes drug resistance in CML

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.