Abstract
Reduced Paired box 5 (PAX5) levels have important roles in the pathogenesis of human B-cell acute lymphoblastic leukemia. However, the role of PAX5 in human lymphoma remains unclear. We generated PAX5-silenced cells using mantle cell lymphoma (MCL) as a model system. These PAX5(-) MCL cells exhibited unexpected phenotypes, including increased proliferation in vitro, enhanced tumor infiltration in vivo, robust adhesion to the bone marrow stromal cells and increased retention of quiescent stem-like cells. These phenotypes were attributed to alterations in the expression of genes including p53 and Rb, and to phosphoinositide 3-kinase/mammalian target of rapamycin and phosphorylated signal transducer and activator of transcription 3 pathway hyperactivation. On PAX5 silencing, the MCL cells displayed upregulated interleukin (IL)-6 expression and increased responses to paracrine IL-6. Moreover, decreased PAX5 levels in CD19+ MCL cells correlated with their increased infiltration and progression; thus, PAX5 levels can be used as a prognostic marker independent of cyclin D1 in advanced MCL patients. Importantly, high-throughput screening of 3800 chemical compounds revealed that PAX5(-) MCL cells are highly drug-resistant compared with PAX5 wild-type MCL cells. Collectively, the results of our study support a paradigm shift regarding the functions of PAX5 in human B-cell cancer and encourage future efforts to design effective therapies against MCL.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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B-Lymphocytes / metabolism*
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B-Lymphocytes / pathology
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Cell Adhesion
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Cell Line, Tumor
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Cell Movement
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Cell Proliferation
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Regulation, Neoplastic*
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High-Throughput Screening Assays
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Lymphoma, Mantle-Cell / diagnosis
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Lymphoma, Mantle-Cell / drug therapy
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Lymphoma, Mantle-Cell / genetics*
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Lymphoma, Mantle-Cell / mortality
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / pathology
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Mice
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PAX5 Transcription Factor / antagonists & inhibitors
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PAX5 Transcription Factor / genetics*
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PAX5 Transcription Factor / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Prognosis
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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CCND1 protein, human
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IL6 protein, human
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Interleukin-6
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PAX5 Transcription Factor
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PAX5 protein, human
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Retinoblastoma Protein
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STAT3 Transcription Factor
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STAT3 protein, human
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Tumor Suppressor Protein p53
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Cyclin D1
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MTOR protein, human
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TOR Serine-Threonine Kinases