title: In vivo imaging enables high resolution preclinical trials on patients' leukemia cells growing in mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Terziyska
authors.forename: Catarina
authors.initials: C
authors.lastname: Castro Alves
authors.forename: Volker
authors.initials: V
authors.lastname: Groiss
authors.forename: Katja
authors.initials: K
authors.lastname: Schneider
authors.forename: Katarina
authors.initials: K
authors.lastname: Farkasova
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Harald
authors.initials: H
authors.lastname: Ehrhardt
authors.forename: Renier J
authors.initials: RJ
authors.lastname: Brentjens
authors.forename: Udo
authors.initials: U
authors.lastname: zur Stadt
authors.forename: Martin
authors.initials: M
authors.lastname: Horstmann
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
mesh_terms: D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D058948:Cell Tracking; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D057285:Precision Medicine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051598:Whole Body Imaging; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D008156:Luciferases