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Status |
Public on Mar 01, 2024 |
Title |
Selective translational control by PABPC1 phase separation regulates blast crisis and target therapy resistance of chronic myeloid leukemia |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten CML patients. Accumulating evidence suggests that translational control is crucial for cancer development and progression. Here, we performed high throughput CRISPR/Cas9 screening and identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML-BC progression. PABPC1 preferentially improved the translation efficiency of multiple leukemogenic mRNAs with long and highly structured 5' untranslated regions, including BCR-ABL1 and its TKI-resistant mutants, through forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, but did not affect normal hematopoiesis seriously. More importantly, we identified two novel PABPC1 inhibitors, 1,10-Phen and ML324, which inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identified PABPC1 as a selective translation enhancing factor in CML-BC, the genetic or pharmacological inhibition of which overcame TKI resistance and suppressed BC progression in CML.
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Overall design |
PABPC1-KD RNA-seq and PABPC1 eCLIP-seq datasets.
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Contributor(s) |
Sun C, Chen Z, Ma Y, Yu J |
Citation missing |
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Submission date |
Mar 08, 2022 |
Last update date |
Oct 30, 2024 |
Contact name |
Zhongyang Chen |
E-mail(s) |
zhychen_96@126.com
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Organization name |
School of Basic Medicine, Peking Union Medical College (PUMC)
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Street address |
No.5, Dongdan Santiao, Dongcheng District
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City |
Beijing |
ZIP/Postal code |
100005 |
Country |
China |
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Platforms (1) |
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Samples (8)
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Relations |
BioProject |
PRJNA813859 |