Constitutive activation of NF-κB signaling by NOTCH1 mutations in chronic lymphocytic leukemia

Xu,Zhen-Shu; Zhang,Ju-Shun; Zhang,Jing-Yan; Wu,Shun-Quan; Xiong,Dong-Lian; Chen,Hui-Jun; Chen,Zhi-Zhe; Zhan,Rong

doi:10.3892/or.2015.3762

April-2015 Volume 33 Issue 4

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April-2015 Volume 33 Issue 4

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Constitutive activation of NF-κB signaling by NOTCH1 mutations in chronic lymphocytic leukemia

Authors:
- Zhen-Shu Xu
- Ju-Shun Zhang
- Jing-Yan Zhang
- Shun-Quan Wu
- Dong-Lian Xiong
- Hui-Jun Chen
- Zhi-Zhe Chen
- Rong Zhan
View Affiliations / Copyright

Affiliations: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China

Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Pages: 1609-1614
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Published online on: January 29, 2015

https://doi.org/10.3892/or.2015.3762
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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.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Constitutive activation of NF-κB signaling by NOTCH1 mutations in chronic lymphocytic leukemia

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