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

Triviai, Ioanna; Ziegler, Marion; Bergholz, Ulla; Oler, Andrew J.; Stübig, Thomas; Prassolov, Vladimir; Kozak, Christine A.; Kröger, Nicolaus; Stocking, Carol

doi:10.1073/pnas.1401215111

Cited by 31 publications

(30 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Induced expression of MuLV ERVs and the subsequent generation of recombinant viruses can have unanticipated phenotypic consequences in xenograft experiments designed to model human diseases. Mice homozygous for Prkdc scid and Il2rg null xenografted with human primary myelofibrosis showed a high frequency of acute myeloid leukemia that was of mouse origin [ 162 ]. The somatically acquired MuLV insertions in the mouse tumors were clonal, and integration was observed in Evi1 , a common integration site for virus-induced myeloid leukemia [ 162 , 163 ].…”

Section: Origins Of Infectious Mulvsmentioning

confidence: 99%

Origins of the Endogenous and Infectious Laboratory Mouse Gammaretroviruses

Kozak¹

2014

Viruses

View full text Add to dashboard Cite

Abstract:The mouse gammaretroviruses associated with leukemogenesis are found in the classical inbred mouse strains and in house mouse subspecies as infectious exogenous viruses (XRVs) and as endogenous retroviruses (ERVs) inserted into their host genomes. There are three major mouse leukemia virus (MuLV) subgroups in laboratory mice: ecotropic, xenotropic, and polytropic. These MuLV subgroups differ in host range, pathogenicity, receptor usage and subspecies of origin. The MuLV ERVs are recent acquisitions in the mouse genome as demonstrated by the presence of many full-length nondefective MuLV ERVs that produce XRVs, the segregation of these MuLV subgroups into different house mouse subspecies, and by the positional polymorphism of these loci among inbred strains and individual wild mice. While some ecotropic and xenotropic ERVs can produce XRVs directly, others, especially the pathogenic polytropic ERVs, do so only after recombinations that can involve all three ERV subgroups. Here, I describe individual MuLV ERVs found in the laboratory mice, their origins and geographic distribution in wild mouse subspecies, their varying ability to produce infectious virus and the biological consequences of this expression.

show abstract

Section: Origins Of Infectious Mulvsmentioning

confidence: 99%

Origins of the Endogenous and Infectious Laboratory Mouse Gammaretroviruses

Kozak¹

2014

Viruses

View full text Add to dashboard Cite

show abstract

“…The nature of the ERV antigen(s) that drive islet autoimmunity and the underlying mechanism that triggers disease onset are poorly understood. Interestingly, when NOD mice are immunodeficient, an endogenous MLV, emv30, is able to replicate to cause primary cancer . This suggests that the intact immune system in normal circumstance is necessary to suppress ERV expression or re‐activation, and also raises the possibility that a similar ERV‐induced immune activation triggers islet autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice

et al. 2017

View full text Add to dashboard Cite

Secreted microvesicles (MVs) are potent inflammatory triggers that stimulate autoreactive B and T cells, causing Type 1 Diabetes in non-obese diabetic (NOD) mice. Proteomic analysis of purified MVs released from islet cells detected the presence of endogenous retrovirus (ERV) antigens, including Env and Gag sequences similar to the well-characterized murine leukemia retroviruses. This raises the possibility that ERV antigens may be expressed in the pancreatic islets via MV secretion. Using virus-like particles produced by co-expressing ERV Env and Gag antigens, and a recombinant gp70 Env protein, we demonstrated that NOD but not diabetes-resistant mice developed anti-Env autoantibodies that increase in titer as disease progresses. A lentiviral-based RNA interference knockdown of Gag revealed that Gag contributes to the MV-induced T-cell response, whose diabetogenic function can be demonstrated via cell-transfer into immune-deficient mice. Finally, we observed that Gag and Env are expressed in NOD islet-derived primary mesenchymal stem cells (MSCs). However, MSCs derived from the islets of diabetes-resistant mice do not express the antigens. Taken together, abnormal ERV activation and secretion of MVs may induce anti-retroviral responses to trigger autoimmunity.

show abstract

“…Genomic copies of HERVs are of particular interest because in addition to functional viral genes, they have multitude of regulatory DNA regions serving as promoters [1][2][3], enhancers [4,5], polyadenylation signals [6,7], insulators [8,9] and binding sites for various nuclear proteins [2,[10][11][12][13]. Many families of HERVs exhibit high transcriptional activity in human tissues [1,[14][15][16][17]. HERVs are believed to be remnants of numerous retroviral infections [18][19][20] that occurred repeatedly during primate evolution [18,21].…”

Section: Introductionmentioning

confidence: 99%

Molecular functions of human endogenous retroviruses in health and disease

Suntsova

Garazha

Ivanova

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

show abstract

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

Cited by 31 publications

References 45 publications

Origins of the Endogenous and Infectious Laboratory Mouse Gammaretroviruses

Origins of the Endogenous and Infectious Laboratory Mouse Gammaretroviruses

Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice

Molecular functions of human endogenous retroviruses in health and disease

Contact Info

Product

Resources

About