Human endogenous retrovirus np9 gene is over expressed in chronic lymphocytic leukemia patients Sabrina Fischer a , Natalia Echeverría a , Gonzalo Moratorio a,c , Ana Inés Landoni d , Guillermo Dighiero b , Juan Cristina a , Pablo Oppezzo b , Pilar Moreno a,b,n a Laboratory of Molecular Virology, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay b Protein Recombinant Unit, Institut Pasteur, Montevideo, Uruguay c Department of Virology, Institut Pasteur, Paris, France d Service of Hematology and Bone Marrow Transplantation, Hospital Maciel, Montevideo, Uruguay article info Article history: Received 17 March 2014 Received in revised form 6 June 2014 Accepted 24 June 2014 Available online 25 July 2014 Keywords: HERVs np9 CLL abstract The human genome contains a large number of endogenous retroviruses (HERVs). Their reactivation has frequently been observed in patients with cancer. Considering their role in the carcinogenesis process, we aimed to study the possible relationship between HERVs gene expression and Chronic Lymphocytic Leukemia (CLL). We focused on two viral genes gag and np9, the latter presumably an oncogene. We found that the transcriptional activity of HERV-K np9 gene was greater in CLL patients than in healthy donors. However, gag expression was not significantly increased. These findings suggest a noteworthy relationship between CLL disease and HERV-K np9 expression. & 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). 1. Introduction Human endogenous retroviruses (HERVs) are genetic remnants of ancient retroviral infections of the germ line produced during primate evolution which are now transmitted vertically. To date, approximately 8% of the human genome is composed of such retroviral sequences [1]. Most HERVs are dysfunctional due to numerous mutations and deletions. However, those belonging to HERV-K family, contain sequences which are likely to be transcribed. Many of these HERVs are transcribed and translated under normal physiological conditions. Nevertheless, reactivation of HERVs has frequently been observed in a variety of human tumors suggest- ing their potential to contribute to malignant progression [2]. Specifically during hemato-oncological processes, several studies have reported the presence of antibodies against HERV-K, over- expression of HERV genes and also the presence of retroviral particles in primary leukemia cells [2]. In addition, np9, a small regulatory gene encoded by HERV-K, has a role as a potent viral oncogene and as a critical molecular switch of multiple signaling pathways regulat- ing the growth of certain human myeloid and lymphoblastic leuke- mia cells [3]. CLL is the most common form of leukemia in Western countries and mainly affects elderly individuals. It follows an extremely variable course, with survival ranging from months to decades. Available treatments often induce disease remission, but almost all patients will relapse and there is a consensus that CLL remains incurable. To date, both an unmutated (UM) profile of immuno- globulin (Ig) VH genes as well as the presence of genetic lesions at chromosome 17p13, or at 11q23 constitute poor prognosis indica- tors [4]. Several studies have begun to shed light on the nature of genetic predisposition of CLL but the basis of this disorder remains unknown [4,5]. Studies that screened for the presence of a virus expressed at the RNA level in human CLL, by using massive sequencing technology, gave no evidence of a putative exogenous viral candidate as a cause for this disease [6]. In order to gain insight into the role of endogenous retrovirus in leukemogenesis, we studied np9 and gag gene expression of HERV-K in Chronic Lymphocytic Leukemia (CLL) patients com- pared to healthy donors. The results revealed that 70% of CLL patients express np9 gene at least 5 times higher than healthy donors, and 33% express gag gene twice as high as normal donors. These findings suggest a significant relationship between CLL disease and HERV-K np9 (and possibly gag) expression. Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/lrr Leukemia Research Reports http://dx.doi.org/10.1016/j.lrr.2014.06.005 2213-0489/& 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). n Corresponding author at: Laboratory of Molecular Virology, Centro de Investi- gaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay E-mail addresses: sfischer@cin.edu.uy (S. Fischer), necheverria@cin.edu.uy (N. Echeverría), gonzamoratorio@gmail.com (G. Moratorio), ailandoni@yahoo.com (A.I. Landoni), dighiero@pasteur.edu.uy (G. Dighiero), cristina@cin.edu.uy (J. Cristina), poppezzo@pasteur.edu.uy (P. Oppezzo), pmoreno@cin.edu.uy (P. Moreno). Leukemia Research Reports 3 (2014) 70–72