title: An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging.
abstract: Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups.
authors: Group Apoptosis, Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Binje
authors: B
authors: Vick
authors: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
authors: Maja
authors: M
authors: Rothenberg
authors: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany; Clinical Cooperation Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Nadine
authors: N
authors: Sandhöfer
authors: Group Apoptosis, Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Michela
authors: M
authors: Carlet
authors: Group Apoptosis, Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Cornelia
authors: C
authors: Finkenzeller
authors: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany; Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Christina
authors: C
authors: Krupka
authors: Group Apoptosis, Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Michaela
authors: M
authors: Grunert
authors: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.
authors: Andreas
authors: A
authors: Trumpp
authors: Department of Pediatrics, University of Regensburg, Regensburg, Germany.
authors: Selim
authors: S
authors: Corbacioglu
authors: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karls Universität, Tuebingen, Germany.
authors: Martin
authors: M
authors: Ebinger
authors: Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karls Universität, Tuebingen, Germany; Department of Pediatric Intensive Care Medicine, University Children's Hospital (UKBB), Basel, Switzerland.
authors: Maya C
authors: MC
authors: André
authors: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany; Clinical Cooperation Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Wolfgang
authors: W
authors: Hiddemann
authors: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
authors: Stephanie
authors: S
authors: Schneider
authors: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany; Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Marion
authors: M
authors: Subklewe
authors: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany; Clinical Cooperation Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Klaus H
authors: KH
authors: Metzeler
authors: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany; Clinical Cooperation Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors: Karsten
authors: K
authors: Spiekermann
authors: Group Apoptosis, Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Oncology, Dr von Haunersches Kinderspital, Ludwig Maximilians-Universität (LMU), Munich, Germany.
authors: Irmela
authors: I
authors: Jeremias
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005818:Genetic Engineering; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008163:Luminescent Measurements / Q000379:methods*; D051379:Mice; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays