Identification of Differentially Expressed Human Endogenous Retrovirus Families in Human Leukemia and Lymphoma Cell Lines and Stem Cells

Abstract

Endogenous retroviruses (ERVs) are becoming more and more relevant in cancer research and might be potential targets. The oncogenic potential of human ERVs (HERVs) has been recognized and includes immunosuppression, cell fusion, antigenicity of viral proteins, and regulation of neighboring genes. To decipher the role of HERVs in human cancers, we used a bioinformatics approach and analyzed RNA sequencing data from the LL-100 panel, covering 22 entities of hematopoietic neoplasias including T cell, B cell and myeloid malignancies. We compared HERV expression in this panel with hematopoietic stem cells (HSCs), embryonic stem cells (ESCs) and normal blood cells. RNA sequencing data were mapped against a comprehensive synthetic viral metagenome with 116 HERV sequences from 14 different HERV families. Of these, 13 HERV families and elements were differently expressed in malignant hematopoietic cells and stem cells. We found transcriptional upregulation of HERVE family in acute megakaryocytic and erythroid leukemia and of HERVFc family in multiple myeloma/plasma cell leukemia (PCL). The HERVFc member HERVFc-1 was found transcriptionally active in the multiple myeloma cell line OPM-2 and also in the Hodgkin lymphoma cell line L-428. The expression of HERVFc-1 in L-428 cells was validated by qRT-PCR. We also confirm transcriptional downregulation of ERV3 in acute megakaryocytic and erythroid leukemia, and HERVK in acute monocytic and myelocytic leukemia and a depression of HERVF in all malignant entities. Most of the higher expressed HERV families could be detected in stem cells including HERVK (HML-2), HERV-like, HERVV, HERVT, ERV9, HERVW, HERVF, HERVMER, ERV3, HERVH and HERVPABLB.

Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression

“…Interestingly, nine HERV families and elements, such as HERV-K, HERV-like, HERV-V, HERV-T, HERV-W and HER2V-F, respectively, were significantly up-regulated in both hESCs and human hematopoietic stem cells (hHSCs) [151] suggesting that certain HERV elements might also play a role in the maintenance of a stem cell state in somatic stem cells. Moreover, a differential expression of HERV families and elements was also found in malignant hematopoietic cells, such as transcriptional upregulation of HERV-E family in acute megakaryocytic and erythroid leukemia, upregulation of HERV-Fc in multiple myeloma/plasma cell leukemia, and down-regulation of HERV-K in acute myeloma [151]. Whether differential expression levels of these HERV elements might contribute to the pathogenesis of such hematopoietic disorders by cancer cell fusion is not yet clear.…”

Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis

“…To investigate the increase in HERVs in LCL and especially in MS samples, we mapped the reads against a synthetic virus metagenome including more than 100 individual HERV sequences [ 44 ]. As also exogenous viruses, like EBV, were included in this mapping process, we observed a distinct increase in EBNA-1 in LCL compared to PBMCs as expected.…”

“…These observations suggest ongoing EBV (re-)activation that might challenge the immune homeostasis directly or by transactivation of HERVs. Besides the antiviral defense, HERVs seem to be involved in the maintenance of the pluripotency of stem cells [ 44 ] and are activated at specific developmental stages during embryogenesis and pregnancy, which also challenges the mentioned host–virus balance [ 73 ]. In summary, HERVs are able to regulate the host genes’ activity in several ways and at different expression levels.…”

“…Additional RNAseq data from activated B cells were downloaded from SRA (BioProjects PRJNA397793 [ 42 ] and PRJNA702159 [ 43 ]). Quantification of overall HERV expression was performed as described [ 44 ] by using the Galaxy server [ 45 ] for Bowtie2 mapping and quantification by FeatureCounts [ 46 ]. Quantification of human transcriptome data was performed by Novogene UK Co., Ltd. (Cambridge, UK) using human genome version GRCh38/hg38.…”

Overexpression of Endogenous Retroviruses and Malignancy Markers in Neuroblastoma Cell Lines by Medium-Induced Microenvironmental Changes

“…All sequences were collected from the nucleotide database from the National Center for Biotechnology Information (NCBI). For detailed information, refer to Engel et al (45). The Galaxy server at usegalaxy.org (46) was used for mapping of the paired-end reads by Bowtie2 analysis and quantification of all uniquely mapped reads using FeatureCounts (47).…”