Svi3: A provirus common integration site in c‐myc in SL/Kh pre‐B lymphomas

Abstract

t has been shown that retroviral insertions in host DNA may cause hematopoietic malignancies by enhancing the expression of a proto-oncogene or by disrupting tumor suppressor genes at the integration sites.1) Recent progress in the technique of retrotransposon tagging has greatly facilitated the identification of cancer-related genes.2) SL/Kh, a pre-B lymphoma-prone inbred mouse strain, provides a unique model to investigate the host genetic and epigenetic factors determining susceptibility and types of disease. 3)Mice of this strain develop spontaneous pre-B lymphomas at >90% incidence by 6 months of age. 4) Several lines of evidence indicate that the endogenous murine leukemia virus (MuLV) plays an etiologic role in the genesis of SL/Kh lymphoma. 5-7)Somatically acquired proviruses are frequently observed in the genomic DNAs of lymphomas. 6) By applying inverse polymerase chain reaction (IPCR), we have identified a number of virus integration hot spots in SL/Kh lymphoma DNA; we have named them SL/Kh virus integration sites (Svi) and numbered them serially in the order of discovery. 7) Svi3 is one of them, in which 3 out of 60 SL/Kh lymphomas had clonal integration of a provirus of the ecotropic MuLV within the promoter region and the first exon of the c-myc. The c-myc encodes a transcription factor that is a cellular homologue of the viral transforming gene encoded by the avian myelocytomatosis virus MC29. 8)Leukemias and lymphomas induced by retroviruses frequently have integration in or near the c-myc gene, 9,10) suggesting that these tumors are clonal or semi-clonal outgrowths of cells that acquired a selective growth advantage in vivo as a consequence of c-myc insertions. In this report, we will describe the provirus integrations at Svi3 and their biological effects in SL/Kh mouse lymphomagenesis. Materials and MethodsMouse strain. SL/Kh is an inbred mouse strain maintained in

Clonal proliferation of HTLV-1-infected cells is associated with spontaneous malignant tumor formation in mice

“…It is well established that clonal growth of MuLV-infected cells results from insertional mutagenesis through integration in or around various growthrelated genes (15,16). A similar mechanism was recently proposed for ATL (17,18).…”

STAT5A Modulates Chemokine Receptor CCR6 Expression and Enhances Pre‐B Cell Growth in a CCL20‐Dependent Manner

“…The inbred mice with leukemogenic retroviral genomes were used in this study and were obtained from the RIKEN Bioresource Center, Japan (http://www.riken.jp/engn/index.html). This strain is derived from the AKR/J strain and is highly susceptible to B-cell leukemia/ lymphoma [Tsuruyama et al, 2002[Tsuruyama et al, , 2011Hiai et al, 2003;Jin et al, 2003]. In the current study, we refer to these mice as spontaneous lymphoma (SL) mice.…”

“…STAT5A PHOSPHORYLATION WAS CORRELATED WITH CCR6 EXPRESSION STAT5A is phosphorylated through the IL-7R/JAK/STS5A [Sasai et al, 2011] pathway and translocates to the nucleus, promoting the transcription of c-Myc and Bcl-xL [Tsuruyama et al, 2002;Jin et al, 2003]. For assessment of STAT5 phosphorylation and correlation with CCR6 expression, 1.0 Â 10 3 pre-B akv/w lymphoma cells were stained using fluorescent immunohistochemistry with anti-pSTAT5A and anti-CCR6 antibodies.…”

Hotspots of MLV integration in the hematopoietic tumor genome

“…46, 47, 48 Here we reviewed MLV integration sites within the c-myc promoter area in particular. As mentioned previously, the systematic analysis did not elucidate a definite trend.…”