Generation and characterization of bioluminescent xenograft mouse models of MLL-related acute leukemias and in vivo evaluation of luciferase-targeting siRNA nanoparticles.
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 down modulation 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.
Department of Pediatric Oncology and Hematology, Sant' Orsola                     Hospital, University of Bologna, Bologna, Italy.
Raffaella
R
Fazzina
Lorenza
L
Lombardini
Laura
L
Mezzanotte
Aldo
A
Roda
Patrizia
P
Hrelia
Andrea
A
Pession
Roberto
R
Tonelli
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000378:metabolism; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics*; D008163:Luminescent Measurements; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D053758:Nanoparticles / Q000008:administration & dosage*; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D051598:Whole Body Imaging
C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; D049409:Luciferases, Firefly; D011495:Histone-Lysine N-Methyltransferase