The truncate mutation of Notch2 enhances cell proliferation through activating the NF-κB signal pathway in the diffuse large B-cell lymphomas

Xinxia Zhang; Yaoyao Shi; Yuanyuan Weng; Qian Lai; Taobo Luo; Jing Zhao; Guoping Ren; Wande Li; Hongyang Pan; Yuehai Ke; Wei Zhang; Qiang He; Qingqing Wang; Ren Zhou

doi:10.1371/journal.pone.0108747

The truncate mutation of Notch2 enhances cell proliferation through activating the NF-κB signal pathway in the diffuse large B-cell lymphomas

PLoS One. 2014 Oct 14;9(10):e108747. doi: 10.1371/journal.pone.0108747. eCollection 2014.

Authors

Xinxia Zhang¹, Yaoyao Shi¹, Yuanyuan Weng¹, Qian Lai¹, Taobo Luo¹, Jing Zhao², Guoping Ren², Wande Li³, Hongyang Pan⁴, Yuehai Ke¹, Wei Zhang¹, Qiang He⁵, Qingqing Wang⁶, Ren Zhou¹

Affiliations

¹ Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
² Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
⁴ Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China; Epitomics (Hangzhou) Inc., Hangzhou, China.
⁵ Zhejiang Province People's Hospital, Hangzhou, China.
⁶ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

The Notch2 is a critical membrane receptor for B-cell functions, and also displays various biological roles in lymphoma pathogenesis. In this article, we reported that 3 of 69 (4.3%) diffuse large B-cell lymphomas (DLBCLs) exhibited a truncate NOTCH2 mutation at the nucleotide 7605 (G/A) in the cDNA sequence, which led to partial deletion of the C-terminal of PEST (proline-, glutamic acid-, serine- and threonine-rich) domain. The truncate Notch2 activated both the Notch2 and the NF-κB signals and promoted the proliferation of B-cell lymphoma cell lines, including DLBCL and Burkitt's lymphoma cell lines. Moreover, the ectopic proliferation was completely inhibited by ammonium pyrrolidinedithiocarbamate (PDTC), an NF-κB inhibitor. Simultaneously, PDTC also reduced the expression level of Notch2. Based on these results, we conclude that the Notch2 receptor with PEST domain truncation enhances cell proliferation which may be associated with the activation of the Notch2 and the NF-κB signaling. Our results are expected to provide a possible target for new DLBCL therapies by suppressing the Notch2 and the NF-κB signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Base Sequence
Burkitt Lymphoma / metabolism
Burkitt Lymphoma / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / genetics
Exons
HEK293 Cells
Humans
Lymphoma, Large B-Cell, Diffuse / metabolism
Lymphoma, Large B-Cell, Diffuse / pathology
Mutagenesis, Site-Directed
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism*
Protein Structure, Tertiary
Pyrrolidines / pharmacology
Receptor, Notch2 / chemistry
Receptor, Notch2 / genetics
Receptor, Notch2 / metabolism*
Signal Transduction*
Thiocarbamates / pharmacology

Substances

Antineoplastic Agents
NF-kappa B
Pyrrolidines
Receptor, Notch2
Thiocarbamates
pyrrolidine dithiocarbamic acid

Grants and funding

This work was supported by grants from the Science Foundation of the National Program on Key Basic Research Project (973) (No. 2014CB542101) who played an important role in data collection and analysis, decision to publish and preparation of the manuscript; by Zhejiang Province (No. Y2090167 and No. 2009C33039) who had a role in study design, data collection and analysis; and by the National Science Foundation of China (No. 30670810) who had a role in study design, data collection and analysis.