Chenguang Sun # 1 2, Xi Xu # 3 4, Zhongyang Chen # 1, Fanqi Zhou # 1, Wen Wang 1, Junzhu Chen 3, Mengyao Sun 1, Fang Wang 1 2, Linjia Jiang 5, Ming Ji 6, Siqi Liu 1, Jiayue Xu 1, Manman He 1, Bowei Su 1, Xiaoling Liu 1, Yingdai Gao 7, Hui Wei 7, Jian Li 8, Xiaoshuang Wang 9 10 11, Meng Zhao 12 13, Jia Yu 14 15, Yanni Ma 16 17

Nat Cell Biol. 2025 Apr;27(4):683-695.

PMID: 40102686 DOI: 10.1038/s41556-024-01607-4

Abstract

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukaemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten patients with CML. Accumulating evidence suggests that translational control is crucial for cancer progression. Our high-throughput CRISPR-Cas9 screening identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML progression in the BC stage. PABPC1 preferentially improved the translation efficiency of multiple leukaemogenic mRNAs with long and highly structured 5' untranslated regions by forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, with minimal effects on normal haematopoiesis. Moreover, we identified two PABPC1 inhibitors that inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identifies PABPC1 as a selective translation enhancing factor in CML-BC, with its genetic or pharmacological inhibition overcoming TKI resistance and suppressed BC progression.

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