دورية أكاديمية
Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1.
العنوان: | Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1. |
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المؤلفون: | Teo AE; Center for Stem Cell and Regenerative Medicine, Brown Foundation, Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, TX, USA., Chen Z; Center for Stem Cell and Regenerative Medicine, Brown Foundation, Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, TX, USA., Miranda RN; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., McDonnell T; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Medeiros LJ; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., McCarty N; Center for Stem Cell and Regenerative Medicine, Brown Foundation, Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, TX, USA. |
المصدر: | Leukemia [Leukemia] 2016 Mar; Vol. 30 (3), pp. 580-93. Date of Electronic Publication: 2015 May 15. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2000- : London : Nature Publishing Group, Specialist Journals Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987- |
مواضيع طبية MeSH: | Gene Expression Regulation, Neoplastic*, B-Lymphocytes/*metabolism , Drug Resistance, Neoplasm/*genetics , 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 |
مستخلص: | 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. |
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معلومات مُعتمدة: | R01 CA181319 United States CA NCI NIH HHS; UL1 TR000371 United States TR NCATS NIH HHS |
المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (CCND1 protein, human) 0 (IL6 protein, human) 0 (Interleukin-6) 0 (PAX5 Transcription Factor) 0 (PAX5 protein, human) 0 (Retinoblastoma Protein) 0 (STAT3 Transcription Factor) 0 (STAT3 protein, human) 0 (Tumor Suppressor Protein p53) 136601-57-5 (Cyclin D1) EC 2.7.1.1 (MTOR protein, human) EC 2.7.11.1 (TOR Serine-Threonine Kinases) |
تواريخ الأحداث: | Date Created: 20150616 Date Completed: 20160719 Latest Revision: 20211203 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC4644730 |
DOI: | 10.1038/leu.2015.140 |
PMID: | 26073757 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1476-5551 |
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DOI: | 10.1038/leu.2015.140 |