ena-STUDY-GIGA-R University of Liege-10-02-2017-13:42:37:177-102
RNA-seq reveals cis-perturbation of key host genes by the HTLV-1/BLV proviruses
An estimated 10 to 20 million humans and 50 million dairy cattle are infected with the closely-related Human T-cell leukemia virus type-1 (HTLV-1) and Bovine Leukemia Virus (BLV) respectively. These retroviruses infect T (HTLV-1) and B (BLV) lymphocytes, provoking an asymptomatic polyclonal expansion that will evolve into an aggressive lethal monoclonal leukemia in ~5% of individuals following decades of latency. It is generally assumed that early oncogenic changes are largely dependent on virus-encoded products and especially the trans-activating effects of the Tax and HTLV-1 bZIP HBZ oncoproteins, while progression to acute leukemia/lymphoma involves somatic mutations in cancer drivers, yet that both are independent of proviral integration site that has been found to be very variable between tumors. Using RNA-seq we demonstrate that HTLV-1/BLV proviruses are integrated in the vicinity of cancer drivers which they perturb either by provirus-dependent transcription termination or as a result of viral antisense RNA-dependent cis-perturbation.  RNA-seq of ATLs (HTLV-1) and B-cell tumors (BLV) revealed in all tumors (i) the complete absence of viral 5’LTR-dependent sense transcripts (corresponding to the gag, pol, env structural genes and the regulatory genes including tax) and (ii) abundant 3’LTR-dependent antisense transcripts (3’AS) corresponding to HTLV-1 Hbz and BLV As1/2 RNAs. Additionally, mapping the RNA reads to the proviral and host reference genomes uncovered 5’LTR-dependent transcriptional termination of the interrupted gene in ~23 % of the tumors. In the remaining ~77 % of the tumors, this revealed the systematic interactions between the viral antisense transcripts (3’AS) and host genes located upstream of the provirus.
An estimated 10 to 20 million humans and 50 million dairy cattle are infected with the closely-related Human T-cell leukemia virus type-1 (HTLV-1) and Bovine Leukemia Virus (BLV) respectively. These retroviruses infect T (HTLV-1) and B (BLV) lymphocytes, provoking an asymptomatic polyclonal expansion that will evolve into an aggressive lethal monoclonal leukemia in ~5% of individuals following decades of latency. It is generally assumed that early oncogenic changes are largely dependent on virus-encoded products and especially the trans-activating effects of the Tax and HTLV-1 bZIP HBZ oncoproteins, while progression to acute leukemia/lymphoma involves somatic mutations in cancer drivers, yet that both are independent of proviral integration site that has been found to be very variable between tumors. Using RNA-seq we demonstrate that HTLV-1/BLV proviruses are integrated in the vicinity of cancer drivers which they perturb either by provirus-dependent transcription termination or as a result of viral antisense RNA-dependent cis-perturbation.  RNA-seq of ATLs (HTLV-1) and B-cell tumors (BLV) revealed in all tumors (i) the complete absence of viral 5’LTR-dependent sense transcripts (corresponding to the gag, pol, env structural genes and the regulatory genes including tax) and (ii) abundant 3’LTR-dependent antisense transcripts (3’AS) corresponding to HTLV-1 Hbz and BLV As1/2 RNAs. Additionally, mapping the RNA reads to the proviral and host reference genomes uncovered 5’LTR-dependent transcriptional termination of the interrupted gene in ~23 % of the tumors. In the remaining ~77 % of the tumors, this revealed the systematic interactions between the viral antisense transcripts (3’AS) and host genes located upstream of the provirus.