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Cis-Perturbation of Cancer Drivers by the HTLV-1/BLV Proviruses Is an Early Determinant of Leukemogenesis

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Cis-Perturbation of Cancer Drivers by the HTLV-1/BLV Proviruses Is an Early Determinant of Leukemogenesis ARTICLE Received 4 Dec 2016 | Accepted 14 Mar 2017 | Published 23 May 2017 DOI: 10.1038/ncomms15264 OPEN Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis Nicolas Rosewick1,2,*, Keith Durkin1,*, Maria Artesi1,*, Ambroise Marc¸ais3, Vincent Hahaut1, Philip Griebel4, Natasa Arsic4,Ve´ronique Avettand-Fenoel5, Arse`ne Burny2, Carole Charlier1, Olivier Hermine3,6, Michel Georges1 & Anne Van den Broeke1,2 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 B5% 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. 1 Unit of Animal Genomics, GIGA-R, Universite´ de Lie`ge (ULg), Avenue de l’Hoˆpital 11, B34, Lie`ge 4000, Belgium. 2 Laboratory of Experimental Hematology, Institut Jules Bordet, Universite´ Libre de Bruxelles (ULB), Boulevard de Waterloo 121, Brussels 1000, Belgium. 3 Service d’he´matologie, Hoˆpital Universitaire Necker, Universite´ Rene´ Descartes, Assistance publique hoˆpitaux de Paris, 149-161 rue de Se`vres, Paris 75010, France. 4 Vaccine and Infectious Disease Organization, VIDO-Intervac, University of Saskatchewan, 120 Veterinary Road, Saskatoon, Canada S7N 5E3. 5 Laboratoire de Virologie, AP-HP, Hoˆpital Necker-Enfants Malades, Universite´ Paris Descartes, Sorbonne Paris Cite´, EA7327, 149 rue de Se`vres, Paris 75010, France. 6 INSERM U1163-ERL8254, Institut Imagine, 24 B Boulevard du Montparnasse, Paris 75010, France. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to A.Vd.B. (email: [email protected]). NATURE COMMUNICATIONS | 8:15264 | DOI: 10.1038/ncomms15264 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15264 n estimated 10–20 million people are infected with unknown. Like HTLV-1, BLV expresses antisense transcripts, the Human T-cell leukaemia virus type-1 (HTLV-1) AS1 and AS2, driven by 30LTR-dependent promoter activity and Aworldwide1.InB5% of infected individuals the virus constitutively produced in leukaemic cells24. In addition, BLV provokes adult T-cell leukaemia/lymphoma (ATL), an aggressive strongly expresses RNA polymerase III-dependent microRNAs T-cell malignancy with a poor prognosis2. Bovine leukaemia overlapping AS1 and contributing to B40% of microRNAs in the virus (BLV) is closely related to HTLV-1 and causes a very similar tumour cell25. B-cell leukaemia in cattle and sheep3,4. The virus In the fraction of infected individuals who do progress, many infects B50 million dairy cattle worldwide inducing substantial years separate the initial infection from the development economic costs in infected herds5. Like HTLV-1 in humans, of leukaemia/lymphoma. This indicates that infection with following a long period of asymptomatic infection (several years BLV/HTLV-1 is not sufficient to provoke tumour development in cattle, several decades in humans) B5% of BLV-infected and that secondary events are required to make the transition animals develop leukaemia/lymphoma. In addition to infecting to a neoplasm. A recent study examined the landscape of bovines, it is possible to experimentally infect sheep with BLV, mutations in ATLs and found frequent alterations enriched in providing a powerful model for studying deltaretrovirus-induced T-cell related pathways and immunosurveillance11. As regards tumours6,7. In contrast to cattle, infected sheep systematically BLV-induced tumours, beyond limited studies that reported develop leukaemia/lymphoma and in a shorter time frame frequent genome instability and mutation of p53 (refs 26,27), the (B20 months). A further advantage of this model is that it is occurrence of secondary events in BLV malignancies remains possible to monitor animals from before infection to terminal largely unexplored. leukaemia/lymphoma, recapitulating many of the stages observed As BLV and HTLV-1 vary little in sequence both within and in HTLV-1-associated human malignancy. between hosts, and as wide variations exist in clone abundance Despite a long history of study in both the HTLV-1 and BLV between infected individuals and over time, it is hypothesized that models, key steps on the road from initial infection to leukaemia the proviral integration site is the principal attribute that development remain poorly elucidated. In chronic stages of distinguishes one infected cell clone from the other, thus is infection, HTLV-1 and BLV propagate primarily through a key element on the road to malignancy. Using a quantitative clonal expansion of infected T- or B-cells, respectively, resulting high-throughput sequencing (HTS) approach to characterize the in the presence of multiple clones of varying abundance each genomic environment of the provirus, previous studies have uniquely identified by their proviral integration site in the host addressed the role of the genomic integration site in determining genome. Following a protracted incubation period, one of clonal expansion and the potential for malignant transformation these clones expands, leading to the accumulation of malignant of cells carrying integrated HTLV-1 or BLV8–10,28,29. Although cells in the peripheral blood (leukaemia) and/or diverse tissues HTLV-1 and BLV preferentially integrate in transcriptionally (lymphoma)4,8–10. Tumour cells consist of a predominant active genomic regions, near transcriptional start sites and malignant T- or B-cell clone and chiefly harbour a single transcription factor-binding sites, there was no reported integrated provirus, yet integration sites are very variable10–12.As evidence of recurrent proviral integration. In tumours, there a consequence, it has been widely believed that virus-encoded were no clear hotspots of HTLV-1/BLV integration associated products drive clonal proliferation and influence oncogenic with leukaemic clones, although the ontology of the nearest progression. Historically the focus of research in BLV/HTLV-1 downstream gene was associated with malignant clones in 6% of has been on the oncogenic potential of the viral TAX protein. the ATL cases10,12. TAX can immortalize rodent cells in vitro and induces tumours Despite the variability of integration sites in fully transformed in transgenic mice, supporting the hypothesis that it is an cells, a role for proviral integration and cis-perturbation of host essential contributor to oncogenesis13,14. TAX activates genes in HTLV-1/BLV-induced clonal expansion cannot be transcription of the provirus and of many host genes, promotes excluded. Here, to explore this hypothesis, we carried out cell-cycle progression and interacts with DNA repair RNA-seq of primary tumours in both the human disease and mechanisms15,16. However, the lack of TAX (and other viral the animal model in combination with HTS mapping of proviral sense transcript) expression in the majority of BLV/HTLV-1- integration sites. We show that HTLV-1/BLV proviruses are induced malignancies and the high frequency of proviruses integrated in the vicinity of cancer drivers, which they perturb containing alterations inactivating TAX points to a more either by provirus-dependent transcription termination or as complicated picture17–20. While TAX expression provides a a result of viral antisense RNA-dependent cis-perturbation. proliferative advantage to the infected clone, it also makes this The same pattern is observed at asymptomatic stages of the clone a target for cytotoxic immune response21. Therefore, it may disease, indicating that provirus-dependent host gene perturba- be advantageous for the virus to evade the strong immune tion triggers initial amplification of the corresponding response to TAX by silencing expression from the positive strand. clones, requiring additional alterations to develop full-blown It is thus widely accepted that TAX fulfils an essential role at early leukaemia/lymphoma. stages of the oncogenic process, yet is not required for late-stage precipitation to monoclonal malignancy. Over the last years it has become increasingly apparent that Results another viral product, HTLV-1 basic leucine zipper (bZIP) factor We obtained samples from 44 adult T-cell leukaemias/lymphoma (HBZ) encoded from the minus-strand, plays an important role (ATLs) (from 35 patients, HTLV-1, human disease) and 47 B-cell in the life cycle and oncogenic potential of the virus. HBZ leukaemias (from 43 individuals, BLV, animal model). The animal downregulates HTLV-1 transcription, promotes T-cell prolifera- sample set included 15 bovine tumours (natural disease) and tion and displays oncogenic properties in transgenic
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