Abstract
Connective tissue growth factor (CTGF/CCN2) is involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in precursor B-acute lymphoblastic leukemia (ALL) and that increased expression of CTGF is associated with inferior outcome in B-ALL. In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knockdown CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA. Silencing of CTGF resulted in significant suppression of leukemia cell growth compared to control vector, which was associated with AKT/mTOR inactivation and increased levels of cyclin-dependent kinase inhibitor p27. CTGF knockdown sensitized ALL cells to vincristine and methotrexate. Treatment with an anti-CTGF monoclonal antibody, FG-3019, significantly prolonged survival of mice injected with primary xenograft B-ALL cells when co-treated with conventional chemotherapy (vincristine, L-asparaginase and dexamethasone). Data suggest that CTGF represents a targetable molecular aberration in B-ALL, and blocking CTGF signaling in conjunction with administration of chemotherapy may represent a novel therapeutic approach for ALL patients.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use*
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Asparaginase / administration & dosage
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Asparaginase / therapeutic use
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Cell Line, Tumor
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Child
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Connective Tissue Growth Factor / antagonists & inhibitors*
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Connective Tissue Growth Factor / genetics
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Connective Tissue Growth Factor / metabolism
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Dexamethasone / administration & dosage
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Dexamethasone / therapeutic use
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Gene Silencing
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Humans
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Mice
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Mice, SCID
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Molecular Targeted Therapy*
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Signal Transduction / drug effects
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Tumor Burden / drug effects
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Tumor Cells, Cultured
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Vincristine / administration & dosage
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Vincristine / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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CCN2 protein, human
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Neoplasm Proteins
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Connective Tissue Growth Factor
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Vincristine
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Dexamethasone
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Asparaginase
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pamrevlumab