Selective translational control by PABPC1 phase separation regulates blast crisis and therapy resistance in chronic myeloid leukaemia

被引：1

作者：

Chenguang Sun ^{[1
]}

Xi Xu ^{[2
]}

Zhongyang Chen ^{[3
]}

Fanqi Zhou ^{[4
]}

Wen Wang ^{[1
]}

Junzhu Chen ^{[1
]}

Mengyao Sun ^{[1
]}

Fang Wang ^{[3
]}

Linjia Jiang ^{[1
]}

Ming Ji ^{[1
]}

Siqi Liu ^{[2
]}

Jiayue Xu ^{[5
]}

Manman He ^{[6
]}

Bowei Su ^{[1
]}

Xiaoling Liu ^{[1
]}

Yingdai Gao ^{[1
]}

Hui Wei ^{[1
]}

Jian Li ^{[1
]}

Xiaoshuang Wang ^{[7
]}

Meng Zhao ^{[7
]}

Jia Yu ^{[8
]}

Yanni Ma ^{[1
]}

机构：

[1] 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, Chines

[2] Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu

[3] Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou

[4] Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou

[5] Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou

[6] Institute of Materia Medica and Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin

[7] State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing

[8] Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing

[9] State Key Laboratory for Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, School of Basic Medicine Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing

来源：

Nature Cell Biology | 2025年 / 27卷 / 4期

基金：

中国国家自然科学基金;

关键词：

D O I：

10.1038/s41556-024-01607-4

中图分类号：

学科分类号：

摘要：

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. © The Author(s), under exclusive licence to Springer Nature Limited 2025.

引用

页码：683 / 695

页数：12

共 66 条

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