Sun Chenguang, Xu Xi, Chen Zhongyang, Zhou Fanqi, Wang Wen, Chen Junzhu, Sun Mengyao, Wang Fang, Jiang Linjia, Ji Ming, Liu Siqi, Xu Jiayue, He Manman, Su Bowei, Liu Xiaoling, Gao Yingdai, Wei Hui, Li Jian, Wang Xiaoshuang, Zhao Meng, Yu Jia, Ma Yanni
State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of RNA and Hematopoietic Regulation, Institute of Basic Medical Sciences, School of Basic Medicine Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, China.
Nat Cell Biol. 2025 Apr;27(4):683-695. doi: 10.1038/s41556-024-01607-4. Epub 2025 Mar 18.
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.
靶向BCR-ABL1融合酪氨酸激酶的酪氨酸激酶抑制剂（TKIs）彻底改变了慢性髓性白血病（CML）的治疗方法。然而，TKI耐药性的出现以及随后从慢性期（CP）向急变期（BC）的转变对CML患者构成了威胁。越来越多的证据表明，翻译控制对癌症进展至关重要。我们的高通量CRISPR-Cas9筛选确定多聚腺苷酸结合蛋白细胞质1（PABPC1）是CML在急变期进展的驱动因素。PABPC1通过形成生物分子凝聚物，优先提高了多个具有长且高度结构化5'非翻译区的致白血病mRNA的翻译效率。抑制PABPC1可显著抑制CML细胞增殖并减缓疾病进展，对正常造血的影响最小。此外，我们鉴定出两种PABPC1抑制剂，它们在小鼠和人类CML中均能抑制急变期进展并克服TKI耐药性。总体而言，我们的研究确定PABPC1是CML-急变期的一种选择性翻译增强因子，对其进行基因或药理学抑制可克服TKI耐药性并抑制急变期进展。
