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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 December 3, 2018; First published September 27, 2018
Citation Information: J Clin Invest. 2018;128(12):5517-5530. https://doi.org/10.1172/JCI122533.
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Categories: Research Article Hematology Oncology

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 1

MYC-regulated kinome in lymphoma.

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MYC-regulated kinome in lymphoma.
(A) Generation of isogenic BCL-2–expre...
(A) Generation of isogenic BCL-2–expressing (MYC Tet-repressible) P493-6 B lymphoma cells. (B) Generation of isogenic BCL-2–expressing Raji and Namalwa BL cells. (C) Generation of isogenic CRISPR/cas9-mediated MYC KO/KD derivatives of Raji and Namalwa BL cells. (D) Schematic work flow of ABPP studies. (E) Overlap of kinases whose activity is upregulated by MYC in P493-6, Namalwa, and Raji BL cells (upper panel) and list of MYC-upregulated kinases (lower panel). (F) KEGG pathway analysis of MYC-upregulated kinome in models of DHL. See complete unedited blots in the supplemental material.
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