title: Constitutive activation of NF-κB signaling by NOTCH1 mutations in chronic lymphocytic leukemia.
abstract: NOTCH1 mutations occur in approximately 10% of patients with chronic lymphocytic leukemia (CLL). However, the relationship between the genetic aberrations and tumor cell drug resistance or disease progression remains unclear. Frameshift deletions were detected by gene sequencing in the NOTCH1 PEST domain in three naive CLL patients. These mutations were associated with chromosomal abnormalities including trisomy 12 or 13q deletion. Of note, one of the patients developed Richter's transformation during FCR treatment. Immunofluorescent and western blot analyses revealed a markedly higher intracellular domain of NOTCH (ICN) expression in the mutated cells compared with their unmutated counterparts and normal CD19+ B lymphocytes (P<0.01 and P<0.001, respectively). In addition, strong DNA-κB binding activities were observed in the mutant cells by gel shift assays. RT-PCR analysis revealed elevated RelA mRNA expression in the mutant cells, while RelB levels were variable. Reduced levels of RelA and RelB mRNA were observed in unmutated CLL and normal B cells. Compared to unmutated CLL and normal B cells, increased apoptosis occurred in the mutant cells in the presence of GSI (ICN inhibitor) and PDTC (NF-κB inhibitor), particularly under the synergistic effects of the two drugs (P=0.03). Moreover, IKKα and IKKβ, the active components in the NF-κB pathway, were markedly inhibited following prolonged treatment with GSI and PDTC. These results suggested that NOTCH1 mutations constitutively activate the NF-κB signaling pathway in CLL, which is likely related to ICN overexpression, indicating NOTCH1 and NF-κB as potential therapeutic targets in the treatment of CLL.
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Zhen-Shu
authors: ZS
authors: Xu
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Ju-Shun
authors: JS
authors: Zhang
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Jing-Yan
authors: JY
authors: Zhang
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Shun-Quan
authors: SQ
authors: Wu
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Dong-Lian
authors: DL
authors: Xiong
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Hui-Jun
authors: HJ
authors: Chen
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Zhi-Zhe
authors: ZZ
authors: Chen
authors: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors: Rong
authors: R
authors: Zhan
mesh_terms: D000368:Aged; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D009842:Oligopeptides; D011392:Proline / Q000031:analogs & derivatives; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D013859:Thiocarbamates; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D051841:Transcription Factor RelB / Q000096:biosynthesis / Q000235:genetics; D014314:Trisomy
chemical_list: D004273:DNA, Neoplasm; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D009842:Oligopeptides; C498143:RELA protein, human; C497593:RELB protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051881:Receptor, Notch1; D013859:Thiocarbamates; D051996:Transcription Factor RelA; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; C066229:prolinedithiocarbamate; D051841:Transcription Factor RelB; D011392:Proline
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