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Leukemia ; 30(3): 580-93, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26073757

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.


Subject(s)
B-Lymphocytes/metabolism , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Lymphoma, Mantle-Cell/genetics , PAX5 Transcription Factor/genetics , Animals , Antineoplastic Agents/pharmacology , B-Lymphocytes/pathology , Cell Adhesion , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cyclin D1/genetics , Cyclin D1/metabolism , High-Throughput Screening Assays , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Lymphoma, Mantle-Cell/diagnosis , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/mortality , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Mice , PAX5 Transcription Factor/antagonists & inhibitors , PAX5 Transcription Factor/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Prognosis , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays
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