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

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. ShainJulie Marie Vose, John L. Cleveland, Eduardo M. Sotomayor, Kai Fu, Jianguo Tao

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5531-5548
Number of pages18
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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B-Cell Lymphoma
Phosphotransferases
Lymphoma
polo-like kinase 1
Protein Stability
Oncogene Proteins
Proteomics
Cell Survival
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. / Ren, Yuan; Bi, Chengfeng; Zhao, Xiaohong; Lwin, Tint; Wang, Cheng; Yuan, Ji; Silva, Ariosto S.; Shah, Bijal D.; Fang, Bin; Li, Tao; Koomen, John M.; Jiang, Huijuan; Chavez, Julio C.; Pham, Lan V.; Sudalagunta, Praneeth R.; Wan, Lixin; Wang, Xuefeng; Dalton, William S.; Moscinski, Lynn C.; Shain, Kenneth H.; Vose, Julie Marie; Cleveland, John L.; Sotomayor, Eduardo M.; Fu, Kai; Tao, Jianguo.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5531-5548.

Research output: Contribution to journalArticle

Ren, Y, Bi, C, Zhao, X, Lwin, T, Wang, C, Yuan, J, Silva, AS, Shah, BD, Fang, B, Li, T, Koomen, JM, Jiang, H, Chavez, JC, Pham, LV, Sudalagunta, PR, Wan, L, Wang, X, Dalton, WS, Moscinski, LC, Shain, KH, Vose, JM, Cleveland, JL, Sotomayor, EM, Fu, K & Tao, J 2018, 'PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5531-5548. https://doi.org/10.1172/JCI122533
Ren, Yuan ; Bi, Chengfeng ; Zhao, Xiaohong ; Lwin, Tint ; Wang, Cheng ; Yuan, Ji ; Silva, Ariosto S. ; Shah, Bijal D. ; Fang, Bin ; Li, Tao ; Koomen, John M. ; Jiang, Huijuan ; Chavez, Julio C. ; Pham, Lan V. ; Sudalagunta, Praneeth R. ; Wan, Lixin ; Wang, Xuefeng ; Dalton, William S. ; Moscinski, Lynn C. ; Shain, Kenneth H. ; Vose, Julie Marie ; Cleveland, John L. ; Sotomayor, Eduardo M. ; Fu, Kai ; Tao, Jianguo. / PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5531-5548.
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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.",
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T1 - PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas

AU - Ren, Yuan

AU - Bi, Chengfeng

AU - Zhao, Xiaohong

AU - Lwin, Tint

AU - Wang, Cheng

AU - Yuan, Ji

AU - Silva, Ariosto S.

AU - Shah, Bijal D.

AU - Fang, Bin

AU - Li, Tao

AU - Koomen, John M.

AU - Jiang, Huijuan

AU - Chavez, Julio C.

AU - Pham, Lan V.

AU - Sudalagunta, Praneeth R.

AU - Wan, Lixin

AU - Wang, Xuefeng

AU - Dalton, William S.

AU - Moscinski, Lynn C.

AU - Shain, Kenneth H.

AU - Vose, Julie Marie

AU - Cleveland, John L.

AU - Sotomayor, Eduardo M.

AU - Fu, Kai

AU - Tao, Jianguo

PY - 2018/12/3

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N2 - 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.

AB - 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.

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