Abstract
Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 32 patients with smoldering, chronic, lymphoma and acute leukemia using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared with normal lymphocytes. Several unique genes were identified that were overexpressed in leukemic cells, including TNFSF11, RGS13, MAFb, CSPG2, C/EBP-alpha, and TCF4; 200 of the most highly overexpressed ATL genes were analyzed by the Pathway Studio, version 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, proliferating cell nuclear antigen, and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells with BIRC5 shRNA decreased BIRC5 expression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Adult
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Aged
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Boronic Acids / therapeutic use
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Bortezomib
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CD4-Positive T-Lymphocytes / metabolism
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Cell Survival
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Daclizumab
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Down-Regulation
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics*
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Humans
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Immunoglobulin G / therapeutic use
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Inhibitor of Apoptosis Proteins
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Leukemia-Lymphoma, Adult T-Cell / drug therapy
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Leukemia-Lymphoma, Adult T-Cell / genetics
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Leukemia-Lymphoma, Adult T-Cell / metabolism*
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Leukemia-Lymphoma, Adult T-Cell / pathology*
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Male
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Middle Aged
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Pyrazines / therapeutic use
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RNA Interference
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Survivin
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Transcription Factor 4
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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BIRC5 protein, human
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Boronic Acids
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DNA-Binding Proteins
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Immunoglobulin G
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Pyrazines
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Survivin
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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Bortezomib
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Daclizumab