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.
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This study is supported in part by grants from the National Institutes of Health Lymphoma SPORE (CA136411), P01 “The Therapy of AML” (CA55164), Leukemia SPORE (CA100632), Cancer Center Support Grant (CA16672), the Paul and Mary Haas Chair in Genetics (M. Andreeff) and by 1R01CA155056-01, CDP-01, Leukemia and Lymphoma Society and DRP, and Leukemia Spore 5 P50 CA100632-08 (to M. Konopleva).
Conflict of interest
S.S. is an employee of FibroGen, a biopharmaceutical company that develops anti-CTGF monoclonal antibody.
Hongbo Lu and Kensuke Kojima contributed equally to this project.
Electronic supplementary material
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CTGF knockdown inhibits REH cell proliferation. (a) Growth curves of REH cells expressing either empty vector (EV) or CTGF shRNA (shCTGF). Statistically significant differences are denoted as follows: **p < 0.01, ***p < 0.001. (b) Cell cycle profiles of REH cells expressing either empty vector (EV) or CTGF shRNA (shCTGF). (DOC 446 kb) (DOC 446 kb)
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Lu, H., Kojima, K., Battula, V.L. et al. Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth. Ann Hematol 93, 485–492 (2014). https://doi.org/10.1007/s00277-013-1939-2