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PLoS One. 2015 Mar 20;10(3):e0120925. doi: 10.1371/journal.pone.0120925. eCollection 2015.

An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging.

Author information

1
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.
2
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
3
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.
4
Group Apoptosis, Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
5
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.
6
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.
7
Department of Pediatrics, University of Regensburg, Regensburg, Germany.
8
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.
9
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.
10
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.
11
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.
12
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.

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.

PMID:
25793878
PMCID:
PMC4368518
DOI:
10.1371/journal.pone.0120925
[Indexed for MEDLINE]
Free PMC Article

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