Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis
نویسندگان
چکیده
Human T-cell leukaemia virus type-1 (HTLV-1) and bovine leukaemia virus (BLV) infect T- and B-lymphocytes, respectively, provoking a polyclonal expansion that will evolve into an aggressive monoclonal leukaemia in ∼5% of individuals following a protracted latency period. It is generally assumed that early oncogenic changes are largely dependent on virus-encoded products, especially TAX and HBZ, while progression to acute leukaemia/lymphoma involves somatic mutations, yet that both are independent of proviral integration site that has been found to be very variable between tumours. Here, we show that HTLV-1/BLV proviruses are integrated near cancer drivers which they affect either by provirus-dependent transcription termination or as a result of viral antisense RNA-dependent cis-perturbation. The same pattern is observed at polyclonal non-malignant stages, indicating that provirus-dependent host gene perturbation contributes to the initial selection of the multiple clones characterizing the asymptomatic stage, requiring additional alterations in the clone that will evolve into full-blown leukaemia/lymphoma.
منابع مشابه
Mechanisms of pathogenesis induced by bovine leukemia virus as a model for human T-cell leukemia virus
Bovine leukemia virus (BLV) and human T-cell leukemia virus type 1 (HTLV-1) make up a unique retrovirus family. Both viruses induce chronic lymphoproliferative diseases with BLV affecting the B-cell lineage and HTLV-1 affecting the T-cell lineage. The pathologies of BLV- and HTLV-induced infections are notably similar, with an absence of chronic viraemia and a long latency period. These viruses...
متن کاملMassive Depletion of Bovine Leukemia Virus Proviral Clones Located in Genomic Transcriptionally Active Sites during Primary Infection
Deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) induce a persistent infection that remains generally asymptomatic but can also lead to leukemia or lymphoma. These viruses replicate by infecting new lymphocytes (i.e. the infectious cycle) or via clonal expansion of the infected cells (mitotic cycle). The relative importance of these two cycles...
متن کاملSerological and genomic detection of bovine leukemia virus in human and cattle samples
Bovine leukemia virus (BLV) is a retrovirus responsible for lymphoproliferative disorders in cattle. Although infections of BLV in animals are well known, little is known about its capacity to infect humans. This study investigated the presence of anti-BLV antibodies and BLV proviruses in human and cattle samples. An indirect enzyme-linked immunosorbent assay (ELISA) was used to detect anti-BL...
متن کاملSerological and genomic detection of bovine leukemia virus in human and cattle samples
Bovine leukemia virus (BLV) is a retrovirus responsible for lymphoproliferative disorders in cattle. Although infections of BLV in animals are well known, little is known about its capacity to infect humans. This study investigated the presence of anti-BLV antibodies and BLV proviruses in human and cattle samples. An indirect enzyme-linked immunosorbent assay (ELISA) was used to detect anti-BL...
متن کاملGene activation therapy: from the BLV model to HAM/TSP patients.
HTLV-1 (human T-lymphotropic virus type 1) and BLV (bovine leukemia virus) are two related retroviruses infecting CD4+ and B lymphocytes in humans and ruminants, respectively. During infection, the host-pathogen interplay is characterized by very dynamic kinetics resulting in equilibrium between the virus, which attempts to proliferate, and the immune response, which seeks to exert tight contro...
متن کامل