title: Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis.
abstract: The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdc(scid) and Il2rg(null) alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation.
authors.affiliation: Retrovirus Pathogenesis, Heinrich Pette Institute, Leibniz Institute of Experimental Virology, 20251 Hamburg, Germany;Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Ioanna
authors.initials: I
authors.lastname: Triviai
authors.affiliation: Retrovirus Pathogenesis, Heinrich Pette Institute, Leibniz Institute of Experimental Virology, 20251 Hamburg, Germany;
authors.forename: Marion
authors.initials: M
authors.lastname: Ziegler
authors.affiliation: Retrovirus Pathogenesis, Heinrich Pette Institute, Leibniz Institute of Experimental Virology, 20251 Hamburg, Germany;
authors.forename: Ulla
authors.initials: U
authors.lastname: Bergholz
authors.affiliation: Computational Biology Section, Bioinformatics and Computational Biosciences Branch, and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Oler
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Stübig
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Prassolov
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892; and.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Kozak
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Retrovirus Pathogenesis, Heinrich Pette Institute, Leibniz Institute of Experimental Virology, 20251 Hamburg, Germany; carol.stocking@hpi.uni-hamburg.de.
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
mesh_terms: D000368:Aged; D000818:Animals; D015139:Blotting, Southern; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D009052:Leukemia Virus, Murine / Q000235:genetics; D007942:Leukemia, Experimental / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000473:pathology / Q000821:virology; D011533:Proviruses / Q000235:genetics; D014183:Transplantation, Heterologous; D016662:Virus Integration / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D055815:Young Adult
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit