PABPC1相分离的选择性翻译控制调控慢性髓系白血病细胞危象和治疗抵抗

IF 17.3 1区 生物学 Q1 CELL BIOLOGY
Chenguang Sun, Xi Xu, Zhongyang Chen, Fanqi Zhou, Wen Wang, Junzhu Chen, Mengyao Sun, Fang Wang, Linjia Jiang, Ming Ji, Siqi Liu, Jiayue Xu, Manman He, Bowei Su, Xiaoling Liu, Yingdai Gao, Hui Wei, Jian Li, Xiaoshuang Wang, Meng Zhao, Jia Yu, Yanni Ma
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引用次数: 0

摘要

靶向BCR-ABL1融合酪氨酸激酶的酪氨酸激酶抑制剂(TKIs)已经彻底改变了慢性髓性白血病(CML)的治疗。然而,TKI耐药的发展以及随后从慢性期(CP)到爆炸危象(BC)的转变威胁着CML患者。越来越多的证据表明,转译控制对癌症进展至关重要。我们的高通量CRISPR-Cas9筛选鉴定出多聚(A)结合蛋白细胞质1 (PABPC1)是BC期CML进展的驱动因素。PABPC1通过形成生物分子凝聚体,优先提高具有长且结构高度的5 '非翻译区的多种致白血病mrna的翻译效率。抑制PABPC1显著抑制CML细胞增殖和减缓疾病进展,对正常造血的影响最小。此外,我们发现了两种抑制BC进展的PABPC1抑制剂,并克服了小鼠和人类CML中的TKI耐药性。总的来说,我们的工作确定了PABPC1是CML-BC中的一个选择性翻译增强因子,其遗传或药理抑制克服TKI抗性并抑制BC进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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

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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来源期刊
Nature Cell Biology
Nature Cell Biology 生物-细胞生物学
CiteScore
28.40
自引率
0.90%
发文量
219
审稿时长
3 months
期刊介绍: Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to: -Autophagy -Cancer biology -Cell adhesion and migration -Cell cycle and growth -Cell death -Chromatin and epigenetics -Cytoskeletal dynamics -Developmental biology -DNA replication and repair -Mechanisms of human disease -Mechanobiology -Membrane traffic and dynamics -Metabolism -Nuclear organization and dynamics -Organelle biology -Proteolysis and quality control -RNA biology -Signal transduction -Stem cell biology
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