Gene Expression Profiling of Murine T-Cell Lymphoblastic Lymphoma Identifies Deregulation of S-Phase Initiating Genes.

Abstract 2395

Human T-cell lymphoblastic lymphomas (T-LBLs) are neoplasms of immature T-cells and constitute a group of rare, heterogeneous and clinically very aggressive tumors. The molecular pathogenesis that contributes to T-LBL development is not fully elucidated. Since murine T-LBLs are histopathologically and phenotypically comparable to human T-LBLs, mouse models of T-LBLs are ideal to obtain additional insight into the mechanism of T-LBL development in humans. When injected into newborn mice of the NMRI inbred strain, the SL3-3 murine leukemia virus (MLV) induces various types of hematological malignancies, including T-LBLs. The oncogenic effects of the SL3-3 MLV are caused by integration of the viral genome into the host cell DNA through multiple rounds of infection, and subsequent deregulation of nearby cellular genes – a process defined as insertional mutagenesis. If the integration occurs near or within a gene of importance for cancer development, the cell in which the virus has integrated, may gain a growth advantage, eventually leading to malignant transformation and development of a full blown tumor. Screening the murine genome for resulting integration sites in the end-stage tumors, is therefore an efficient method for identifying genes involved in murine and potentially also human T-cell lymphomagenic processes.

In a search for genes and pathways implicated in T-cell lymphoblastic lymphoma (T-LBL) development, we used a murine lymphoma model, where mice of the NMRI inbred strain were inoculated with mutants of SL3-3 MLV. The mutants were affected in the glucocorticoid response element and an overlapping E-box of the viral enhancer in the long termial releat. By performing integration analysis on 19 and global gene expression profiling on 22 of the resulting T-LBL tumors, we determined both the effect of the retroviral integrations on the summarized expression of the nearby genes, and the deregulated pathways in the tumors. Fifty two different genes were identified within a 10 kb distance of the retroviral integrations, whereof 15 were specifically involved in G₁/S phase transition. Gene expression dot-plots showed an activating effect of the retrovirus on Mr1, Stx6, Cask and Sh3gl3. Gene expression profiling identified increased expression of genes involved in the minichromosome maintenance (Mcm) and origin of recognition (Orc) pathway as well as downregulation in negative regulators of G₁/S transition, indicating that murine T-LBLs have increased S-phase initiation. In conclusion, both the integration analysis and patterns of mRNA expression identified by gene expression profiling in the mouse models of T-LBL strongly indicate that genes involved in G1/S phase transition and/or S-phase initiation are deregulated suggesting similar mechanisms to be of importance in human T-LBL pathogenesis.