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Updated: May 6, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF
Hongbo Lu1, Kensuke Kojima1, Venkata Lokesh Battula1
1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
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.
Insights
Connective tissue growth factor (CTGF) drives B-acute lymphoblastic leukemia (ALL) cell growth. Blocking CTGF with antibodies and chemotherapy improves leukemia treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Connective tissue growth factor (CTGF/CCN2) is implicated in tumor progression, including extracellular matrix production, proliferation, and metastasis.
- Elevated CTGF expression is observed in precursor B-acute lymphoblastic leukemia (B-ALL) and correlates with poorer patient outcomes.
Purpose of the Study:
- To investigate the functional role of CTGF in B-ALL cells.
- To elucidate the downstream signaling pathways regulated by CTGF in B-ALL.
- To evaluate CTGF as a therapeutic target in B-ALL.
Main Methods:
- Lentiviral shRNA was used to knockdown CTGF in RS4;11 and REH B-ALL cell lines.
- Cell growth, AKT/mTOR signaling, and cell cycle regulators were assessed.
- Sensitivity to chemotherapy agents (vincristine, methotrexate) was evaluated.
- Efficacy of an anti-CTGF monoclonal antibody (FG-3019) was tested in a murine xenograft model of B-ALL.
Main Results:
- CTGF knockdown significantly suppressed leukemia cell growth.
- Silencing CTGF led to AKT/mTOR pathway inactivation and increased p27 levels.
- CTGF inhibition sensitized B-ALL cells to vincristine and methotrexate.
- Combined treatment with FG-3019 and chemotherapy significantly improved survival in a B-ALL xenograft model.
Conclusions:
- CTGF plays a critical role in B-ALL cell proliferation and survival.
- Targeting CTGF signaling, particularly in combination with conventional chemotherapy, presents a promising therapeutic strategy for B-ALL.
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