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PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas
Yuan Ren, … , Kai Fu, Jianguo Tao
Yuan Ren, … , Kai Fu, Jianguo Tao
Published September 27, 2018
Citation Information: J Clin Invest. 2018;128(12):5517-5530. https://doi.org/10.1172/JCI122533.
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Research Article Hematology Oncology Article has an altmetric score of 16

PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas

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Abstract

Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression, and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability, and in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the antiapoptotic protein MCL-1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival, and tumorigenicity, supporting clinical targeting of PLK1 in DHL.

Authors

Yuan Ren, Chengfeng Bi, Xiaohong Zhao, Tint Lwin, Cheng Wang, Ji Yuan, Ariosto S. Silva, Bijal D. Shah, Bin Fang, Tao Li, John M. Koomen, Huijuan Jiang, Julio C. Chavez, Lan V. Pham, Praneeth R. Sudalagunta, Lixin Wan, Xuefeng Wang, William S. Dalton, Lynn C. Moscinski, Kenneth H. Shain, Julie Vose, John L. Cleveland, Eduardo M. Sotomayor, Kai Fu, Jianguo Tao

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Figure 4

MYC activates PLK1 transcription in DHL.

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MYC activates PLK1 transcription in DHL.
(A) PLK1 protein levels are dep...
(A) PLK1 protein levels are dependent on MYC. P493-6 cells were cultured with Tet for 72 hours, and a portion were then deprived of Tet for 24 hours. Levels of MYC, PLK1, and β-actin were determined by Western blot. (B) MYC KD by CRISPR/cas9 gene editing provokes reductions in PLK1 protein in DHL DOHH2 and VAL cells. (C) Upper panel: an E-box site that conforms to the preferred binding site for MYC (CACGTG, PLK1-P1) is located approximately 80 base pairs upstream of the PLK1 transcription start site (TSS). Lower panel: ChIP assays revealed MYC binds to this region of the PLK1 promoter in DHL cells. Binding of MYC to the CDK4 promoter was assessed as a positive control. A and B are representative of 3 independent experiments. Data presented in C show the mean ± SD of at least 3 independent experiments. See complete unedited blots in the supplemental material.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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