title: Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/-γc-/- mice.
abstract: Juvenile myelomonocytic leukemia is a clonal malignant disease affecting young children. Current cure rates, even with allogeneic hematopoietic stem cell transplantation, are no better than 50%-60%. Pre-clinical research on juvenile myelomonocytic leukemia is urgently needed for the identification of novel therapies but is hampered by the unavailability of culture systems. Here we report a xenotransplantation model that allows long-term in vivo propagation of primary juvenile myelomonocytic leukemia cells. Persistent engraftment of leukemic cells was achieved by intrahepatic injection of 1×10(6) cells into newborn Rag2(-/-)γc(-/-) mice or intravenous injection of 5×10(6) cells into 5-week old mice. Key characteristics of juvenile myelomonocytic leukemia were reproduced, including cachexia and clonal expansion of myelomonocytic progenitor cells that infiltrated bone marrow, spleen, liver and, notably, lung. Xenografted leukemia cells led to reduced survival of recipient mice. The stem cell character of juvenile myelomonocytic leukemia was confirmed by successful serial transplantation that resulted in leukemia cell propagation for more than one year. Independence of exogenous cytokines, low donor cell number and slowly progressing leukemia are advantages of the model, which will serve as an important tool to research the pathophysiology of juvenile myelomonocytic leukemia and test novel pharmaceutical strategies such as DNA methyltransferase inhibition.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center, Freiburg, Germany Faculty of Biology, University of Freiburg, Germany.
authors.forename: Christopher Felix
authors.initials: CF
authors.lastname: Krombholz
authors.affiliation: Department of Pathology, University Medical Center, Freiburg, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Aumann
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center, Freiburg, Germany Faculty of Biology, University of Freiburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kollek
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center, Freiburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bertele
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center, Freiburg, Germany Hermann Staudinger Graduate School, University of Freiburg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fluhr
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center, Freiburg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Kunze
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center, Freiburg, Germany The German Cancer Consortium, Heidelberg, Germany.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center, Freiburg, Germany The German Cancer Consortium, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center, Freiburg, Germany The German Cancer Consortium, Heidelberg, Germany miriam.erlacher@uniklinik-freiburg.de.
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
mesh_terms: D000818:Animals; D001706:Biopsy; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology; D006801:Humans; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency*; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation / Q000009:adverse effects; D014411:Neoplastic Stem Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D004268:DNA-Binding Proteins; D053631:Interleukin Receptor Common gamma Subunit; C499308:Rag2 protein, mouse