Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 23; pp. 8595 - 8600
• Main Authors: Triviai, Ioanna, Ziegler, Marion, Bergholz, Ulla, Oler, Andrew J., Stübig, Thomas, Prassolov, Vladimir, Fehse, Boris, Kozak, Christine A., Kröger, Nicolaus, Stocking, Carol
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.06.2014; National Acad Sciences
• Subjects: Aged; Animals; Biological Sciences; Blotting, Southern; Bone marrow; Cellular biology; Disease; Endogenous Retroviruses - genetics; Female; Genetic loci; Genetic mutation; Humans; Interleukin Receptor Common gamma Subunit - genetics; Interleukin Receptor Common gamma Subunit - metabolism; Leukemia; Leukemia Virus, Murine - genetics; Leukemia, Experimental - genetics; Leukemia, Experimental - pathology; Leukemia, Experimental - virology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Leukemia, Myeloid, Acute - virology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Middle Aged; Molecular Sequence Data; Murine leukemia virus; Myeloid leukemia; Primary Myelofibrosis - genetics; Primary Myelofibrosis - pathology; Primary Myelofibrosis - virology; Proviruses; Proviruses - genetics; Retroviridae; Rodents; Stem cells; Transplantation, Heterologous; Tumor stem cells; Viral diseases; Virus Integration - genetics; Virus Replication - genetics; Viruses; Young Adult
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1401215111

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.