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.
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
Submitter: Ryan Wilcox | firstname.lastname@example.org
Authors: Carlos Murga-Zamalloa and Ryan Wilcox
University of Michigan
Published February 14, 2019
We have read with interest the manuscript published by Ren et al. By means of an activity-based proteomic profiling (ABPP) the authors demonstrated that polo-like kinase 1 (PLK1) is predominantly activated in B-cell lymphomas that featured increased MYC oncoprotein levels.
Increased levels of MYC oncoprotein is a hallmark of highly aggressive lymphomas. By means of a kinase-specific shRNA library screen, we have also demonstrated increased activation of PLK1 in aggressive T-cell and B-cell lymphomas1. Our findings demonstrated that PLK1 expression correlated with MYC expression, consistent with a phosphorylation-dependent feedback loop between PLK1 and MYC that maintains MYC oncoprotein stability in aggressive lymphomas. Our findings also demonstrated that inhibition of PLK1 with the selective inhibitor volasertib was associated with decreased MYC expression in aggressive lymphomas, and increased apoptosis of tumor cells. Our findings are in agreement with Ren et al. and extend the potential therapeutic use of PLK1 inhibition to aggressive T-cell lymphomas, including peripheral T-cell lymphomas, non-otherwise specified (PTCL-NOS).
1. Murga-Zamalloa C, Polk A, Hanel W, Chowdhury P, Brown N, Hristov AC, Bailey NG, Wang T, Phillips T, Devata S, Poonnen P, Gomez-Gelvez J, Inamdar KV, Wilcox RA. Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas. Oncotarget. Dec 29 2017;8(70):114474-114480.