FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma

Autor: Brad S. Kahl, Lixin Rui, Yangguang Li, Myriam N. Bouchlaka, N Pflum, Christian M. Capitini, David T. Yang, S Qian, Xuehua Zhong, Craig J. Thomas, Kreg M. Grindle, P Jobin, Shelly M. Wuerzberger-Davis, Jens C. Eickhoff, J Wolff, Shigeki Miyamoto, Li Lu
Rok vydání: 2016
Předmět:
0301 basic medicine
Proteasome Endopeptidase Complex
Cancer Research
Cell Survival
Receptors
Antigen
B-Cell
Antineoplastic Agents
Lymphoma
Mantle-Cell
Protein degradation
Article
Small hairpin RNA
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Growth factor receptor
immune system diseases
Cell Line
Tumor
hemic and lymphatic diseases
Agammaglobulinaemia Tyrosine Kinase
Genetics
medicine
Cluster Analysis
Humans
Bruton's tyrosine kinase
neoplasms
Molecular Biology
Sulfonamides
biology
F-Box Proteins
Gene Expression Profiling
NF-kappa B
Protein-Tyrosine Kinases
Bridged Bicyclo Compounds
Heterocyclic
BCL6
medicine.disease
Ubiquitin ligase
Gene Expression Regulation
Neoplastic
030104 developmental biology
Proto-Oncogene Proteins c-bcl-2
chemistry
030220 oncology & carcinogenesis
Ibrutinib
Proteolysis
biology.protein
Cancer research
Mantle cell lymphoma
Signal Transduction
Zdroj: Oncogene. 35:6223-6234
ISSN: 1476-5594
0950-9232
Popis: Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.
Databáze: OpenAIRE
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