In vivo imaging enables high resolution preclinical trials on patients' leukemia cells growing in mice

• Published in: PloS one 2012-12, Vol.7 (12), p.e52798
• Main Authors: Terziyska, Nadia, Castro Alves, Catarina, Groiss, Volker, Schneider, Katja, Farkasova, Katarina, Ogris, Manfred, Wagner, Ernst, Ehrhardt, Harald, Brentjens, Renier J, zur Stadt, Udo, Horstmann, Martin, Quintanilla-Martinez, Leticia, Jeremias, Irmela
• Format: Article
• Language: English
• Subjects: Acute lymphatic leukemia; Acute lymphoblastic leukemia; Adolescent; Animal models; Animals; Antineoplastic Agents - administration & dosage; Biology; Bioluminescence; Biotechnology; Bone imaging; Bone marrow; Bone marrow transplantation; Cancer; Cancer research; Cell number; Cell Tracking; Chemistry; Child; Child, Preschool; Clinical trials; Design parameters; Dilution; Disease; Environmental health; Ethics; Female; Gene Expression; Genetic engineering; Growth; Hematology; Humans; Image resolution; In vivo methods and tests; Infant; Kinases; Leukemia; Light emission; Luciferase; Luciferases - biosynthesis; Luciferases - genetics; Lymphatic leukemia; Male; Medical research; Medicine; Mice; Mice, SCID; Minimal residual disease; Monitoring; Oncology; Patients; Pharmaceuticals; Pharmacy; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Stem cells; Studies; Transplantation; Tumor Burden - drug effects; Tumor cells; Tumor Cells, Cultured; Tumors; Veterinary Science; Whole Body Imaging; Xenograft Model Antitumor Assays - methods; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0052798

Xenograft mouse models represent helpful tools for preclinical studies on human tumors. For modeling the complexity of the human disease, primary tumor cells are by far superior to established cell lines. As qualified exemplary model, patients' acute lymphoblastic leukemia cells reliably engraft in mice inducing orthotopic disseminated leukemia closely resembling the disease in men. Unfortunately, disease monitoring of acute lymphoblastic leukemia in mice is hampered by lack of a suitable readout parameter. Patients' acute lymphoblastic leukemia cells were lentivirally transduced to express the membrane-bound form of Gaussia luciferase. In vivo imaging was established in individual patients' leukemias and extensively validated. Bioluminescence in vivo imaging enabled reliable and continuous follow-up of individual mice. Light emission strictly correlated to post mortem quantification of leukemic burden and revealed a logarithmic, time and cell number dependent growth pattern. Imaging conveniently quantified frequencies of leukemia initiating cells in limiting dilution transplantation assays. Upon detecting a single leukemia cell within more than 10,000 bone marrow cells, imaging enabled monitoring minimal residual disease, time to tumor re-growth and relapse. Imaging quantified therapy effects precisely and with low variances, discriminating treatment failure from partial and complete responses. For the first time, we characterized in detail how in vivo imaging reforms preclinical studies on patient-derived tumors upon increasing monitoring resolution. In the future, in vivo imaging will enable performing precise preclinical studies on a broad range of highly demanding clinical challenges, such as treatment failure, resistance in leukemia initiating cells, minimal residual disease and relapse.