scholarly journals Retrovirus insertion site analysis of LGL leukemia patient genomes

2019 ◽  
Author(s):  
Weiling Li ◽  
Lei Yang ◽  
Robert S. Harris ◽  
Lin Lin ◽  
Thomas L. Olson ◽  
...  
Keyword(s):  
Integration Site ◽  
Insertion Site ◽  
Endogenous Retrovirus ◽  
European Ancestry ◽  
Human Endogenous Retrovirus ◽  
Reference Database ◽  
Leukemia Patient ◽  
Integration Sites ◽  
Retrovirus Integration ◽  
Lgl Leukemia

AbstractBackgroundLarge granular lymphocyte (LGL) leukemia is an uncommon cancer characterized by a sustained clonal proliferation of LGL cells. Antibodies reactive to retroviruses have been documented in the serum of patients with LGL leukemia. Culture or molecular approaches have to date not been successful in identifying a retrovirus.MethodsBecause a retrovirus must integrate into the genome of an infected cell, we focused our efforts on detecting a novel retrovirus integration site in the clonally expanded LGL cells. We present a new computational tool that uses long-insert mate pair sequence data to search the genome of LGL leukemia cells for retrovirus integration sites. We also utilize recently published methods to interrogate the status of polymorphic human endogenous retrovirus type K (HERV-K) provirus in patient genomes.ResultsWhile our analysis did not reveal any new retrovirus insertions in LGL genomes from LGL leukemia patients, we did identify four HERV-K provirus integration sites that are polymorphic in the human population and absent from the human reference genome, hg19. To determine if the prevalence of these or other polymorphic proviral HERV-Ks differed between LGL leukemia patients and the general population, we applied a recently developed approach that reports all sites in the human genome occupied by a proviral HERV-K. Using the 1000 genomes project (KGP) data as a reference database for HERV-K proviral prevalence at each polymorphic site, we show that there are significant differences in the number of polymorphic HERV-Ks in the genomes of LGL leukemia patients of European origin compared to individuals with European ancestry in the KGP data.ConclusionsOur study confirms that the integration of a new infectious or endogenous retrovirus does not cause the clonal expansion of LGL cells in LGL leukemia, although we do not rule out that these cells could be responding to retroviral antigens produced in other cell types. However, it is of interest that the burden of polymorphic proviral HERV-K is elevated in LGL leukemia patient genomes. Our research emphasizes the merits of comprehensive genomic assessment of HERV-K in cancer samples and suggests that further analyses to determine contributions of HERV-K to LGL leukemia are warranted.

A Mouse Model of Evi1-Related Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1958-1958
Author(s):  
Naoko Watanabe-Okochi ◽  
Jiro Kitaura ◽  
Toshio Kitamura ◽  
Mineo Kurokawa
Keyword(s):  
Transcription Factor ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Integration Site ◽  
Leukemic Cells ◽  
Mouse Bone Marrow ◽  
The Novel ◽  
Integration Sites ◽  
Retrovirus Integration ◽  
Common Integration Site

Abstract Abstract 1958 Poster Board I-981 Background: Evi1 gene is located on chromosome 3q26 and aberrantly expressed in acute myeloid leukemia (AML) patients with or without 3q26 abnormalities, and inappropriate expression of Evi1 associates with poor prognosis. Evi-1 is originally identified in a common integration site of murine leukemia retrovirus and enhanced expression of Evi1 by retrovirus integration is thought to be responsible for leukemogenesis in mouse models. However, retroviral expression of marker genes such as GFP has not induced leukemia even if some clones possessing integration at Evi1 site have been identified. These data indicate that Evi1 requires cooperative factors to induce progressive leukemia, whereas overexpression of Evi1 is enough to lead to clonal expansion of hematopoietic cells. Therefore, identifying genes collaborating with Evi1 is one of the key issues of understanding Evi1-related leukemogenesis. Recently, we demonstrated that a point mutation of the transcription factor AML1 (AML1-D171N) can induce myelodysplastic syndrome (MDS) that progresses to AML in association with overexpression of Evi1 through a mouse bone marrow transplantation model. In that work, we analyzed mice transplanted with BM cells transduced Evi1 alone as control and surprisingly confirmed that all of the mice developed leukemia within 6-11 months after the transplant. In this report, we will describe interesting findings in the novel mouse model of Evi1-induced leukemia. Result: C57BL6/Ly-5.1 murine BM cells infected with retroviruses harboring Evi1 were transplanted into irradiated syngeneic Ly-5.2 mice. The mice looked fine until 5 months, but GFP-positive-Evi1 expressing cells were gradually increased in the peripheral blood (PB), and then the mice died at 6-11 months after the transplantation. The mice showed dysplastic features in myeloid and erythroid cells, increase of blasts in the PB and the BM, hepatosplenomegaly, slight anemia, and some of the mice showed severe leukocytosis. The mice were thought to die of multiple organ failure due to invasion of leukemic cells not due to anemia. The phenotype is different from that of the mouse BMT model expressing Evi1 by retrovirus reported by another group, in which the mice died about 10 months with severe peripheral cytopenia and finally the disease did not progress to AML. Therefore, we considered that Evi1 might have collaborated with unknown genes near retrovirus integration sites in our case and analyzed integration sites by the bubble PCR method. Interestingly, frequent integration at 3' side of C/EBPb gene was found in six mice out of eight mice transplanted with Evi1-transduced BM cells. The integrations were located at 62.5-86.7kb downstream of C/EBPb gene. Next, we examined the expression level of C/EBPb, Tmem189, and Ptpn1, all of which are located near the integration site, and confirmed that C/EBPb showed elevated expression although neither Tmem189 nor Ptpn1 did. We also identified Bcas1, Rps6ka1, and Rapgef4 genes at the retroviral integration site in the other two mice without integration near C/EBPb. Discussion: C/EBPb, also known as NF-IL6, is a transcription factor that specifically binds to an IL1-responsive element in the IL-6 gene and has a role in regulation not only for the IL-6 gene but also for several cytokine genes such as TNF, IL-8, and G-CSF. The hematopoietic progenitor cells of C/EBPb-deficient mice have been reported to respond imperfectly to GM-CSF and G-CSF. Furthermore, C/EBPb is a downstream target of the Ras-Raf pathway. The locus of C/EBPb gene has been reported as a common integration site in the Retrovirus Tagged Cancer Gene Database (RTCGD), which is a database of retroviral insertional mutagenesis in mouse tumors. AKxD mice, Cdkn2a-KO mice, NUP98/HOXD13 transgenic mice, and MYC/Runx2 transgenic mice were reported to develop myeloid or lymphoid leukemia by retroviral insertion into 3' side of C/EBPb gene. In this study, we identified frequent integration at 3' side of C/EBPb gene in Evi1-transduced leukemic cells, whereas we have not identified this locus in AML1-mutants-transduced leukemic cells. Based on these findings and our results, C/EBPb is supposed to be a candidate gene to collaborate with Evi1 in leukemogenesis. Conclusion: We identified involvement of C/EBPb in Evi1-induced leukemogenesis. The novel mouse model that we generated in this study could help understanding the molecular basis of Evi1-related leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Retrovirus insertion site analysis of LGL leukemia patient genomes

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Weiling Li ◽  
Lei Yang ◽  
Robert S. Harris ◽  
Lin Lin ◽  
Thomas L. Olson ◽  
...  
Keyword(s):  
Insertion Site ◽  
Site Analysis ◽  
Leukemia Patient ◽  
Lgl Leukemia

Evidence for a functional subclass of the RTVL-H family of human endogenous retrovirus-like sequences.

1993 ◽  
Vol 67 (6) ◽  
pp. 2981-2989 ◽  
Author(s):  
D A Wilkinson ◽  
N L Goodchild ◽  
T M Saxton ◽  
S Wood ◽  
D L Mager
Keyword(s):  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus

Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients

Epigenomics ◽  
2020 ◽  
Vol 12 (19) ◽  
pp. 1689-1706
Author(s):  
Maurizio Cardelli ◽  
Remco van Doorn ◽  
Lares Larcher ◽  
Michela Di Donato ◽  
Francesco Piacenza ◽  
...  
Keyword(s):  
Independent Predictor ◽  
Disease Free Survival ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Free Survival ◽  
Melanocytic Lesions ◽  
Long Interspersed Nuclear Elements ◽  
Melanoma Patients ◽  
And Gender ◽  
Disease Free

Aim: To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Materials & methods: Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions. Results: Methylation levels were lower in melanomas than in nevi. HERV-K and LINE-1 methylation were decreased in melanoma patients with clinical parameters associated with adverse prognosis, while they were independent of age and gender. Hypomethylation of HERV-K (but not LINE-1) was an independent predictor of reduced disease-free survival. Conclusion: HERV-K hypomethylation can be a potential independent biomarker of melanoma recurrence.

scholarly journals HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 449
Author(s):  
Simin D. Rezaei ◽  
Joshua A. Hayward ◽  
Sam Norden ◽  
John Pedersen ◽  
John Mills ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Gag Protein ◽  
Protein Levels ◽  
Prostate Epithelial Cells ◽  
Prostate Cancers

Heightened expression of human endogenous retrovirus (HERV) sequences has been associated with a range of malignancies, including prostate cancer, suggesting that they may serve as useful diagnostic or prognostic cancer biomarkers. We analysed the expression of HERV-K (Gag and Env/Np9 regions), HERV-E 4.1 (Pol and Env regions), HERV-H (Pol) and HERV-W (Gag) sequences in prostate cancer cells lines and normal prostate epithelial cells using qRT-PCR. HERV expression was also analysed in matched malignant and benign prostate tissue samples from men with prostate cancer (n = 27, median age 65.2 years (range 47–70)) and compared to prostate cancer-free male controls (n = 11). Prostate cancer epithelial cell lines exhibited a signature of HERV RNA overexpression, with all HERVs analysed, except HERV-E Pol, showing heightened expression in at least two, but more commonly all, cell lines analysed. Analysis of primary prostate material indicated increased expression of HERV-E Pol but decreased expression of HERV-E Env in both malignant and benign regions of the prostate in men with prostate cancer as compared to those without. Expression of HERV-K Gag was significantly higher in malignant regions of the prostate in men with prostate cancer as compared to matched benign regions and prostate cancer-free men (p < 0.001 for both), with 85.2% of prostate cancers donors showing malignancy-associated upregulation of HERV-K Gag RNA. HERV-K Gag protein was detected in 12/18 (66.7%) malignant tissues using immunohistochemistry, but only 1/18 (5.6%) benign tissue sections. Heightened expression of HERV-K Gag RNA and protein appears to be a sensitive and specific biomarker of prostate malignancy in this cohort of men with prostate carcinoma, supporting its potential utility as a non-invasive, adjunct clinical biomarker.

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