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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\n                    <jats:italic>ZAK<\/jats:italic>\n                    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 translation elongation, and generated nuclease-resistant collided ribosomes that triggered ZAK-dependent p38 activation and apoptosis. Furthermore, pharmacological modulation of translation flux fine-tuned the efficacy of BCR::ABL1 inhibitors, including in primary patient cells. These findings define a ribosome-based stress pathway crucial for CML apoptosis and highlight ZAK-dependent RSR as a therapeutic vulnerability.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02916-3","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:03:58Z","timestamp":1774857838000},"page":"955-969","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["BCR::ABL1 tyrosine kinase inhibitors induce ribosome collisions to activate ZAK-dependent ribotoxic stress and apoptosis in chronic myeloid leukemia"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7411-7696","authenticated-orcid":false,"given":"Jumin","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2521-3197","authenticated-orcid":false,"given":"Soo-Hyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3119-6187","authenticated-orcid":false,"given":"Jongmin","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heeju","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtae","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3967-4267","authenticated-orcid":false,"given":"Dong-Wook","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8473-9272","authenticated-orcid":false,"given":"Chunghun","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"2916_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nsmb.3147","volume":"23","author":"O Brandman","year":"2016","unstructured":"Brandman O, Hegde RS. 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