Abstract
Multilevel genetic characterization of Waldenström macroglobulinemia (WM) is required to improve our understanding of the underlying molecular changes that lead to the initiation and progression of this disease. We performed microRNA-expression profiling of bone marrow-derived CD19(+) WM cells, compared with their normal cellular counterparts and validated data by quantitative reverse-transcription-polymerase chain reaction (qRT-PCR). We identified a WM-specific microRNA signature characterized by increased expression of microRNA-363*/-206/-494/-155/-184/-542-3p, and decreased expression of microRNA-9* (ANOVA; P < .01). We found that microRNA-155 regulates proliferation and growth of WM cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-kappaB pathways. Potential microRNA-155 target genes were identified using gene-expression profiling and included genes involved in cell-cycle progression, adhesion, and migration. Importantly, increased expression of the 6 miRNAs significantly correlated with a poorer outcome predicted by the International Prognostic Staging System for WM. We further demonstrated that therapeutic agents commonly used in WM alter the levels of the major miRNAs identified, by inducing downmodulation of 5 increased miRNAs and up-modulation of patient-downexpressed miRNA-9*. These data indicate that microRNAs play a pivotal role in the biology of WM; represent important prognostic marker; and provide the basis for the development of new microRNA-based targeted therapies in WM.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal, Murine-Derived
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Boronic Acids / administration & dosage
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Bortezomib
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Case-Control Studies
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Cell Adhesion / drug effects
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Cell Cycle / drug effects
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm
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Female
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Flow Cytometry
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Fluorescent Antibody Technique
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Green Fluorescent Proteins / metabolism
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Humans
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Lymphocytes / metabolism
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Lymphocytes / pathology
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Male
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Mice
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MicroRNAs / genetics*
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Middle Aged
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology*
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Oligonucleotide Array Sequence Analysis
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Phosphatidylinositol 3-Kinases / metabolism
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Prognosis
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazines / administration & dosage
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Rituximab
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Signal Transduction
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Waldenstrom Macroglobulinemia / drug therapy*
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Waldenstrom Macroglobulinemia / genetics*
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Waldenstrom Macroglobulinemia / metabolism
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Waldenstrom Macroglobulinemia / pathology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Murine-Derived
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Boronic Acids
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MicroRNAs
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NF-kappa B
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Pyrazines
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RNA, Messenger
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Rituximab
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Bortezomib
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases