In Vivo Imaging Enables High Resolution Preclinical Trials on Patients’ Leukemia Cells Growing in Mice

Abstract

BackgroundXenograft 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.Design and MethodsPatients’ 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.ResultsBioluminescence 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.ConclusionsFor 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.

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

“…697 cells were transduced with the respective viruses and sorted for mCherry-positive cells as described. 28 …”

Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII

“…A549 human lung cancer cells were transduced with a vesicular stomatitis virus G protein-pseudotyped lentivirus encoding GFP and Gaussia luciferase (LUC) essentially as described elsewhere (33). Cells expressing the highest GFP levels were isolated using a Becton Dickinson Aria III cell sorter and amplified, yielding a homogenous population with respect to GFP expression ( Supplementary Fig.…”

“…Also macroscopic post mortem inspection did not reveal any indication for antibody-related tissue and organ damage. Tumor growth rates were monitored by longitudinal measurements of whole body bioluminescence signals (photons/second) using an IVIS Lumina II Imaging System (Caliper Life Sciences) as described (33). Briefly, mice were anesthetized with isofluorane and fixed in the imaging chamber.…”

Orthotopic Xenograft Mouse Model of Cervical Cancer for Studying the Role of MicroRNA-21 in Promoting Lymph Node Metastasis

“…It has been used previously in studies of breast cancer 21,22 and leukemia. 23,24 However, it has not been used to study cervical cancer. We believe that acquiring both anatomic and dynamic information is possible by combining fluorescence and bioluminescent imaging techniques, thus leading to a better understanding of tumorigenesis and response to treatment in cervical cancer.…”