Page 179 - Haematologica April 2020

Non Hodgkin Lymphoma
EZH2 inhibitors abrogate upregulation of trimethylation of H3K27 by CDK9 inhibitors and potentiate its activity against diffuse large B-cell lymphoma
Shao Xie,1,2,# Fan Wei,1,3,# Yi-ming Sun,1 Ying-lei Gao,1 Lu-lu Pan,3,4 Min-jia Tan,4 Shu-dong Wang,5 Jian Ding1 and Yi Chen1
1Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research and Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; 2Key Laboratory of Breast Cancer, and Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; 3University of Chinese Academy of Sciences, Beijing, China; 4Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica and Chinese Academy of Sciences, Shanghai, China and 5Centre for Drug Discovery and Development, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, Adelaide, Australia
#SX and FW are co-first authors.
ABSTRACT
Aberrant expression of CDK9/cyclin T1 has been found in diffuse large B-cell lymphoma (DLBCL), and suggests that CDK9 is a poten- tial therapeutic target for DLBCL. Here, we firstly demonstrated that CDKI-73, a novel cyclin-dependent kinases (CDK) inhibitor, potently blocks CDK9, triggered apoptosis and dramatically repressed DLBCL cell growth owing to CDK9 inhibition. CDK9 inhibitors specifically elevated the trimethylation of H3K27, which we speculate was due to reduced expression of JMJD3/UTX. Considering the important role of the trimethy- lation of H3K27 in tumor progression, the synergistic effect of the combi- nation therapy of CDK9 inhibitors with EZH2 inhibitors was investigated. EZH2 inhibitors reversed the upregulation of trimethylation of H3K27, and synergistically inhibited DLBCL and other solid tumors growth in vitro and in vivo. These findings provide a rational basis for the application of CDK9 inhibitors in combination with EZH2 inhibitors in clinical trials.
Introduction
Diffuselarge B-cell lymphoma (DLBCL) is the most common aggressive lym- phoma, accounting for 30-40% of all Non-Hodgkin lymphoma incidences.1 Despite the fact that the median survival time of DLBCL patients is over 8 years, more than 25-30% of the patients relapse,1 making it necessary to develop more effective ther- apeutics.
CDK9, together with cyclin T/K, is responsible for the transcription elongation of most protein-coding genes through phosphorylating the RNA polymerase II (RNA Pol II) at the ser2 residual.2,3 Similar to other lymphoma sub-types, DLBCL has a deregulated cell cycle. These alterations suggest that inhibitors of cyclin- dependent kinases (CDK) might be beneficial for patients affected by DLBCL.4 Research indicates that CDK9/cyclin T1 is involved in lymphocyte differentiation and activation, and shows an aberrant expression in DLBCL.5 In addition, MCL1 expression, which can be downregulated by CDK9 inhibition,6 was found to be overexpressed in a significant fraction of DLBCL,6,7 contributing to therapy resist- ance.8 All these suggest that CDK9 inhibition seems to be a potential therapeutic strategy for the treatment of DLBCL.
Methylation of lysine 27 on histone H3 (H3K27me), a modification associated with gene repression, plays a critical role in regulating the expression of genes that determine the balance between cell differentiation and proliferation.9 This modifi-
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):1021-1031
Correspondence:
YI CHEN
ychen@simm.ac.cn
JIAN DING
jding@simm.ac.cn
Received: March 26, 2019. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2019.222935
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/1021
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