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

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

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 3

PLK1 sustains MYC protein stability by activating an AKT-GSK3β circuit.

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PLK1 sustains MYC protein stability by activating an AKT-GSK3β circuit. ...
(A) Volasertib treatment (20 nM, 24 hours) reduces steady-state levels of MYC protein in DOHH2, VAL, U2932, CJ, and RC DHL cells. (B) PLK1 KO by CRISPR/cas9 editing provokes marked reductions in MYC protein levels that can be restored by treatment (6 hours) with the proteasome inhibitor MG132 (10 μM). (C) Reductions in MYC protein provoked by volasertib treatment (20 nM, 24 hours) are at least partially blocked by pretreatment (6 hours) with MG132 (10 μM). (D) PLK1 inhibition (volasertib, 20 nM) triggers reductions in MYC and blocks AKT, GSK3β, and ERK1/2 activation in DHL cells. Cells were treated for the indicated intervals and assessed for levels of MYC, p–T58-MYC, p–S62-MYC, β-actin, p–S473-AKT, total AKT, p-ERK1/2, total ERK1/2, p-GSK3β, and total GSK3β. (E) PLK1 KO triggers reductions in MYC and in activation of AKT and GSK3β in DOHH2 and VAL DHL cells. (F and G) GSK3β inhibition with SB216763 (5 μM) (F) or AKT inhibition with MK2206 (G) impairs volasertib-induced reductions of MYC protein in DOHH2 and RC DHL cells. (A–G). Data shown are representative of at least 3 independent experiments. See complete unedited blots in the supplemental material.