Generation and characterization of bioluminescent xenograft mouse models of MLL-related acute leukemias and in vivo evaluation of luciferase-targeting siRNA nanoparticles

Fazzina,Raffaella; Lombardini,Lorenza; Mezzanotte,Laura; Roda,Aldo; Hrelia,Patrizia; Pession,Andrea; Tonelli,Roberto

doi:10.3892/ijo.2012.1504

Generation and characterization of bioluminescent xenograft mouse models of MLL-related acute leukemias and in vivo evaluation of luciferase-targeting siRNA nanoparticles

Authors:
- Raffaella Fazzina
- Lorenza Lombardini
- Laura Mezzanotte
- Aldo Roda
- Patrizia Hrelia
- Andrea Pession
- Roberto Tonelli
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Affiliations: Department of Pediatric Oncology and Hematology, Sant' Orsola Hospital, University of Bologna, Bologna, Italy, Department of Pediatric Oncology and Hematology, Sant' Orsola Hospital, University of Bologna, Bologna, Italy, Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy, Department of Pharmacology, University of Bologna, Bologna, Italy
Published online on: May 31, 2012 https://doi.org/10.3892/ijo.2012.1504
Pages: 621-628

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Abstract

Chromosomal translocations involving the MLL gene on 11q23 present frequent abnormalities in pediatric, adult and therapy-related acute leukemias, and are generally associated with aggressive disease and poor prognosis. Here, we report bioluminescent acute leukemia xenograft mouse models of the most frequent and aggressive MLL-related acute leukemias (infant and adult MLL-AF9, MLL-ENL, MLL-AF4). Four acute leukemia cell lines carrying MLL-related translocations were stably transduced with a firefly luciferase transgene and injected intravenously into NOD/SCID mice. Leukemia progression was monitored by in vivo bioluminescence imaging (BLI). All mice developed MLL-related acute leukemia. The four MLL-related acute leukemia models showed a different course of infant and adult MLL-AF9 acute myeloid leukemia, and a rapid aggressiveness of MLL-ENL acute lymphoblastic leukemia and MLL-AF4 acute biphenotypic leukemia. Tissue analysis and RT-PCR of bone marrow, spleen and liver from the mice confirmed the BL results. To validate BLI for the detection of a therapeutic response, systemic treatment with an anti-luciferase-targeting siRNA (siLuc) complexed with cationic nanoparticles was administered to mice with MLL-AF4 acute lymphoblastic leukemia. The BLI signal showed a reduction following treatment with siLuc compared to the control mice. These mouse models present MLL-related acute leukemia evolution similar to the human counterparts. Moreover, they are non-invasive, rapid and sensitive models, suitable for the in vivo study of MLL-related acute leukemias. Finally, BLI showed in vivo luminescence downmodulation obtained by systemic treatment with luciferase-targeting siRNA nanoparticle complexes, confirming that these MLL-related leukemia mouse models are optimal for the evaluation and selection of delivery systems for siRNA and other new biotechnological pharmaceuticals.

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