BCR::ABL1 tyrosine kinase inhibitors induce ribosome collisions to activate ZAK-dependent ribotoxic stress and apoptosis in chronic myeloid leukemia.

ABSTRACT: Ribosome collisions act as molecular sensors of cellular stress, yet their role in disease physiology remains unclear. Here, we demonstrate that inhibition of the oncogenic kinase BCR::ABL1 in chronic myeloid leukemia (CML) cells induces ribosome collisions and activates the ribotoxic stress response (RSR). Clinical analyses revealed that CML progression from the chronic phase to the aggressive blast phase correlated with elevated expression of the RSR-initiating kinase ZAK. Although ZAK sustained CML cell proliferation by promoting AKT activity, loss of ZAK function paradoxically reduced the cytotoxic effects of BCR::ABL1 inhibitors. Mechanistically, BCR::ABL1 inhibition promoted phosphorylation of eukaryotic translation elongation factor 2 (EEF2) via the mTOR-EEF2K pathway, slowed transl

SUBMITTER: Park J 

PROVIDER: S-EPMC13149316 | biostudies-literature | 2026 May

REPOSITORIES: biostudies-literature