Abstract
3033 Background: Acute lymphocytic leukemia (ALL) is the most common childhood leukemia. In this study, we investigated the antitumor effects of TLR7 agonist (imiquimod) against human B-cell acute lymphocytic leukemia. Methods: Human B-ALL cell lines and purified CD19+CD10+ primary B-ALL cells were analyzed for TLR7 mRNA and protein expression by real-time RT-PCR and by Western blot. In vitro growth and apoptosis of B-ALL cells following TLR7 agonist treatment were determined by cell counts, TMRE staining, Western blot and flow cytometry of the activation/cleavage of caspases. Therapeutic effects of TLR7 agonist against human B-ALL were evaluated in xenograft mouse models, where luciferase-labeled RS4;11 or BLIN-1 cell line were injected into NOD/SCID IL2Rg mice. Cohorts of mice were injected with a lethal dose of RS4;11 or BLIN-1 cells with or without pre-incubation with TLR7 agonist to determine their leukemia development. Therapeutic efficacy of TLR7 agonist was evaluated by determining leukemia cell engraftment, tumor burden, the survival time and rate of the treated mice. Results: Human B-ALL cell lines (6/6 tested) and primary B-ALL cells (8/8 tested) express high levels of TLR7 mRNA and proteins. Triggering TLR7 on B-ALL cells with imiquimod strongly suppresses in vitro growth of B-ALL cell lines (RS4;11, BLIN-1) and induces profound apoptosis of primary B-ALL cells in culture in TLR7 agonist treatment time and dose-dependent manners. Injection of RS4;11 or BLIN-1 leukemia cells into NOD/SCID mice causes disseminated leukemia in multiple organs and resulting in uniform lethality of RS4;11 mice in 8 weeks and BLIN-1 mice in 12 weeks, respectively. Mice receiving TLR7 agonist pretreated B-ALL cells had a significant increase in long-term survival rate and a significant reduction in tumor burden. Administration of TLR7 agonist (daily i.p. injection for 5 days) in mice with B-ALL cells significantly reduced (8.2 to 11.4 fold) leukemia cell burdan and increased long-term survival time and rate of the treated mice. Conclusions: Our results demonstrate that TLR7-targeting directly inhibits the growth and induces apoptotic death of human B-ALL cells in vitro and in vivo, providing new insights into the biology and therapy of B-ALL. No significant financial relationships to disclose.
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