Nuclear Factors That Bind to the U3 Region of Two Murine Myeloid Leukemia-Inducing Retroviruses, Cas-Br-E and Graffi

Abstract

Cas-Br-E and Graffi are two myeloid leukemia-inducing murine viruses. Cas-Br-E induces, in NIH-Swiss mice, mostly non-T, non-B leukemia composed of very immature cells with no specific characteristics (Bergeron et al. (1993). Leukemia 7, 954-962). The Graffi murine leukemia virus causes exclusively myeloid leukemia, but the tumor cells are clearly of granulocytic nature (Ru et al. (1993). J. Virol. 67, 4722). We were interested to understand the role of the long terminal repeat (LTR) U3 region in the myeloid specificity of these two retroviruses. We used DNase I footprinting and gel mobility shift assays to identify a number of protein binding sites within Cas-Br-E and Graffi U3 regions. The pattern of protected regions is highly similar for the two viruses. Some factors identified in other murine leukemia viruses, like the core binding factor, also bind to Cas-Br-E and Graffi LTR; however, other binding sites seem specific for these two viruses. Only one difference between them was noted, at the 5' end of the U3 region. Transcriptional activity of both LTRs was also analyzed in various cell lines and compared with other murine leukemia viruses. The results show a slight myeloid specificity for the two LTRs, and indicate that the Graffi enhancer is quite strong in a broad range of cell types.

Novel Insights into the Pathogenesis of the Graffi Murine Leukemia Retrovirus

“…These variations in latency are more likely explained by the presence of two direct repeats in the GV-1.2 LTR. Probably, this allows the binding of more transcription factors, making it globally more transcriptionally powerful as shown previously (4). GV-1.2 induces a higher percentage of T-cell leukemias.…”

“…This study reveals that the Graffi murine leukemia virus (MuLV) is a complex virus capable to induce a large spectrum of leukemias. It replicates efficiently in several cell types, as already suggested in studies of the LTR (3,4). It is multipotent and induces both lymphoid and nonlymphoid leukemia, including megakaryocytic leukemias, which are quite rare in MuLV-induced pathologies.…”

“…The Graffi retroviruses are capable to infect a very large spectrum of cell types, and the major determinant is very likely due to its LTR. Indeed, we analyzed the Graffi LTR-driven transcriptional activity in several cell lines (4). The U3 region of GV-1.2 was found to be a very strong promoter in all the hematopoietic cell lines tested (erythroid, myeloid, and T-lymphoid).…”

Significance of Murine Retroviral Mutagenesis for Identification of Disease Genes in Human Acute Myeloid Leukemia

“…Second, a virus-flanking gene may be involved in murine but not human AML. This may apply to genes encoding transcription factors that activate promoter and enhancer elements in the virus LTR (17,18). Finally, some genes identified in mice may not be deregulated in human AML at the transcriptional but at the translational/posttranslational level or may be functionally altered due to mutations.…”

A PCR primer system for detecting oncoretroviruses based on conserved DNA sequence motifs of animal retroviruses and its application to human leukaemias and lymphomas

“…Type B and type C viruses are known to act oncogenically by transactivation of genes near their integration site through promoters located in the viral LTRs. The U3 region of the type C LTR contains sequences for control and regulation of viral transcription with binding sites for several factors influencing tissue-specific expression and regulation of expression of both virus-encoded and cellular proteins (Fan, 1997 ; Barat & Rassart, 1998 ). Even in those cases where viral proteins are known to act as oncogenic transactivators, e.g.…”