title: The truncate mutation of Notch2 enhances cell proliferation through activating the NF-κB signal pathway in the diffuse large B-cell lymphomas.
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.
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xinxia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yaoyao
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Weng
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lai
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Taobo
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Ren
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Wande
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China; Epitomics (Hangzhou) Inc., Hangzhou, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Zhejiang Province People's Hospital, Hangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: He
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005091:Exons; D057809:HEK293 Cells; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000494:pharmacology; D051883:Receptor, Notch2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D011759:Pyrrolidines; D051883:Receptor, Notch2; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid