Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts

Zhang, Yu An; Maitra, Anirban; Hsieh, Jer‐Tsong; Rudin, Charles M.; Peacock, Craig D.; Karikari, Collins; Brekken, Rolf A.; Stastny, Victor; Gao, Boning; Girard, Luc; Wistuba, Ignacio I.; Frenkel, Eugene P.; Minna, John D.; Gazdar, Adi F.

doi:10.4161/cbt.12.7.15955

Cited by 25 publications

(46 citation statements)

References 47 publications

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“…Their significance stems from the recombination between the two that ultimately led to the generation of XMRV during the passaging of a human prostate tumor as xenografts in mice. To our knowledge, no other MLV, recombinant or otherwise, acquired by human tissues upon transplantation into mice has ever received this much attention, even though such retroviral acquisitions by heterologous cells occur frequently during passage of human cells in mice or other species and have been known for more than 30 years (1,6,15,56,62,67). Even more frequent is unintentional infection of cell lines with retroviruses in the laboratory, often going unnoticed for many years (3,23,28,41,42,51,54).…”

Section: Figmentioning

confidence: 99%

Characterization, Mapping, and Distribution of the Two XMRV Parental Proviruses

Cingöz

Paprotka

Delviks-Frankenberry

et al. 2012

J Virol

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Xenotropic murine leukemia virus-related virus (XMRV) was previously reported to be associated with human prostate cancer and chronic fatigue syndrome. Our groups recently showed that XMRV was created through recombination between two endogenous murine retroviruses, PreXMRV-1 and PreXMRV-2, during the passaging of a prostate tumor xenograft in nude mice. Here, multiple approaches that led to the identification of PreXMRV-2, as well as the distribution of both parental proviruses among different mouse species, are described. The chromosomal loci of both proviruses were determined in the mouse genome, and integration site information was used to analyze the distribution of both proviruses in 48 laboratory mouse strains and 46 wild-derived strains. The strain distributions of PreXMRV-1 and PreXMRV-2 are quite different, the former being found predominantly in Asian mice and the latter in European mice, making it unlikely that the two XMRV ancestors could have recombined independently in the wild to generate an infectious virus. XMRV was not present in any of the mouse strains tested, and among the wild-derived mouse strains analyzed, not a single mouse carried both parental proviruses. Interestingly, PreXMRV-1 and PreXMRV-2 were found together in three laboratory strains, Hsd nude, NU/NU, and C57BR/cd, consistent with previous data that the recombination event that led to the generation of XMRV could have occurred only in the laboratory. The three laboratory strains carried the Xpr1 n receptor variant nonpermissive to XMRV and xenotropic murine leukemia virus (X-MLV) infection, suggesting that the xenografted human tumor cells were required for the resulting XMRV recombinant to infect and propagate.

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Section: Figmentioning

confidence: 99%

Characterization, Mapping, and Distribution of the Two XMRV Parental Proviruses

Cingöz

Paprotka

Delviks-Frankenberry

et al. 2012

J Virol

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“…X-MLVs were first isolated from cells and tissues of various inbred laboratory mice (3), but these viruses have also been found as contaminants in various human cell lines in searches that were prompted by the identification of the xenotropic murine leukemia virus-related virus (XMRV), an X-MLV contaminant in a human prostate xenograft (62,63). Many of these X-MLVs, such as N417/EKVX, a contaminant of the human SCLC tumor cell line, are virtually identical to Bxv1 (64,65), whereas XMRV is a novel recombinant of two MLV ERV precursors, PreXMRV-1 and PreXMRV-2 (62,66). Other X-MLV contaminants, like DG75, found in a human B-lymphoblastoid cell line (67), are related to but distinct from mouse-derived X-MLVs likely due to their origins from unidentified variant ERVs or because of adaptations to their human host cells.…”

Section: The Origins and Subspecies Distribution Of The Four Y-linkedmentioning

confidence: 99%

Sequence Diversity, Intersubgroup Relationships, and Origins of the Mouse Leukemia Gammaretroviruses of Laboratory and Wild Mice

Bamunusinghe

Naghashfar

Buckler-White

et al. 2016

J Virol

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Mouse leukemia viruses (MLVs) are found in the common inbred strains of laboratory mice and in the house mouse subspecies of Mus musculus. Receptor usage and envelope (env) sequence variation define three MLV host range subgroups in laboratory mice: ecotropic, polytropic, and xenotropic MLVs (E-, P-, and X-MLVs, respectively). These exogenous MLVs derive from endogenous retroviruses (ERVs) that were acquired by the wild mouse progenitors of laboratory mice about 1 million years ago. We analyzed the genomes of seven MLVs isolated from Eurasian and American wild mice and three previously sequenced MLVs to describe their relationships and identify their possible ERV progenitors. The phylogenetic tree based on the receptor-determining regions of env produced expected host range clusters, but these clusters are not maintained in trees generated from other virus regions. Colinear alignments of the viral genomes identified segmental homologies to ERVs of different host range subgroups. Six MLVs show close relationships to a small xenotropic ERV subgroup largely confined to the inbred mouse Y chromosome. env variations define three E-MLV subtypes, one of which carries duplications of various sizes, sequences, and locations in the proline-rich region of env. Outside the env region, all E-MLVs are related to different nonecotropic MLVs. These results document the diversity in gammaretroviruses isolated from globally distributed Mus subspecies, provide insight into their origins and relationships, and indicate that recombination has had an important role in the evolution of these mutagenic and pathogenic agents. IMPORTANCELaboratory mice carry mouse leukemia viruses (MLVs) of three host range groups which were acquired from their wild mouse progenitors. We sequenced the complete genomes of seven infectious MLVs isolated from geographically separated Eurasian and American wild mice and compared them with endogenous germ line retroviruses (ERVs) acquired early in house mouse evolution. We did this because the laboratory mouse viruses derive directly from specific ERVs or arise by recombination between different ERVs. The six distinctively different wild mouse viruses appear to be recombinants, often involving different host range subgroups, and most are related to a distinctive, largely Y-chromosome-linked MLV ERV subtype. MLVs with ecotropic host ranges show the greatest variability with extensive inter-and intrasubtype envelope differences and with homologies to other host range subgroups outside the envelope. The sequence diversity among these wild mouse isolates helps define their relationships and origins and emphasizes the importance of recombination in their evolution. Mouse leukemia viruses (MLVs) with ecotropic, xenotropic, and polytropic host ranges (E-MLVs, X-MLVs, and P-MLVs, respectively) are readily isolated from the classical strains of the laboratory mouse (reviewed in reference 1). E-MLVs can infect murine cells but not cells of heterologous species; these viruses use the amino acid transporter, CAT-...

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“…Some strains are xenotropic and grow efficiently in human cells. Serial transplantation of PDXs, especially SCLC, is associated with a high frequency of xenotropic virus contamination, 27 which poses potential health risks and may influence genetic, immune and metabolic analyses. Unfortunately, the tumors themselves cannot be directly monitored for leukemia virus contamination as the PDXs contain mouse derived cells having numerous copies of the integrated genomes.…”

Section: Resultsmentioning

confidence: 99%

“…Paradoxically, the mouse cells release low or absent levels of the virus, while the infected human cells release enormous amounts. 27 …”

Section: Resultsmentioning

confidence: 99%

From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers

Gazdar

Hirsch

Minna

2016

Journal of Thoracic Oncology

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Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts

Cited by 25 publications

References 47 publications

Characterization, Mapping, and Distribution of the Two XMRV Parental Proviruses

Characterization, Mapping, and Distribution of the Two XMRV Parental Proviruses

Sequence Diversity, Intersubgroup Relationships, and Origins of the Mouse Leukemia Gammaretroviruses of Laboratory and Wild Mice

From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers

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