Abstract
The c-myb oncogene is a frequent target for retroviral activation in hemopoietic tumors of avian and mammalian species. While insertions can target the gene directly, numerous clusters of retroviral insertion sites have been identified which map close to c-myb and outside the transcription unit in T-lymphomas (Ahi-1, fit-1, and Mis-2) and monocytic and myeloid leukemias (Mml1, Mml2, Mml3, and Epi-1). Previous analyses showed no consistent effect of these insertions on c-myb expression, raising the possibility that other nearby genes were the true targets. In contrast, our analysis of four cell lines established from lymphomas bearing insertions at fit-1 (fti-1) (feline leukemia virus) and Ahi-1 (Moloney murine leukemia virus) shows that these display higher expression levels of c-myb RNA and protein compared to a panel of phenotypically similar cell lines lacking such insertions. An interesting feature of the cell lines with long-range c-myb insertions was that each also carried an activated Myc allele. The potential for oncogenic synergy between Myb and Myc in T-cell lymphoma was confirmed in transgenic mice overexpressing alleles of both genes in the T-cell compartment, lending further credence to the case for c-myb as the major target for long-range activation. In contrast, mapping and analysis of c-myb neighboring genes (HBS1 and FLJ20069) showed that the expression of these genes did not correlate well with the presence of proviral insertions. A possible explanation for the paradoxical behavior of c-myb was provided by one of the murine T-lymphoma lines bearing an insertion at Ahi-1 (p/m16i) that reproducibly down-regulated c-myb RNA and protein to very low levels or undetectable levels on prolonged culture. Our observations implicate c-myb as a key target of upstream and downstream retroviral insertions. However, overexpression may become dispensable during outgrowth in vitro, and perhaps during tumor progression in vivo, providing a potential rationale for the previously observed discordance between retroviral insertion and c-myb expression levels.
Overview
- The study investigates the role of c-myb oncogene in hemopoietic tumors of avian and mammalian species, specifically in T-lymphomas and monocytic and myeloid leukemias. The study compares the outcomes observed under different experimental conditions or interventions, including retroviral activation of c-myb and the presence of proviral insertions at specific sites near the gene. The primary objective of the study is to determine the impact of c-myb activation on the expression of the gene and its potential role as a major target for long-range activation in T-cell lymphoma. The study uses cell lines established from lymphomas bearing insertions at fit-1 and Ahi-1, as well as transgenic mice overexpressing alleles of both genes in the T-cell compartment. The study identifies key findings that implicate c-myb as a key target of upstream and downstream retroviral insertions, and suggests that overexpression may become dispensable during outgrowth in vitro and tumor progression in vivo. The study aims to answer the question of the role of c-myb in hemopoietic tumors and its potential as a major target for long-range activation in T-cell lymphoma.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions, including retroviral activation of c-myb and the presence of proviral insertions at specific sites near the gene. The study identifies significant differences in the results between these conditions, specifically in the expression levels of c-myb RNA and protein in cell lines established from lymphomas bearing insertions at fit-1 and Ahi-1. The study also identifies an interesting feature of the cell lines with long-range c-myb insertions, which is that each also carried an activated Myc allele. The potential for oncogenic synergy between Myb and Myc in T-cell lymphoma was confirmed in transgenic mice overexpressing alleles of both genes in the T-cell compartment. The study also identifies a paradoxical behavior of c-myb, where the expression of neighboring genes (HBS1 and FLJ20069) does not correlate well with the presence of proviral insertions. The study suggests that c-myb is a key target of upstream and downstream retroviral insertions, and overexpression may become dispensable during outgrowth in vitro and tumor progression in vivo. The key findings of the study support the hypothesis that c-myb is a major target for long-range activation in T-cell lymphoma and implicate it as a key oncogene in hemopoietic tumors of avian and mammalian species.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice, as they provide evidence for the role of c-myb in hemopoietic tumors and its potential as a major target for long-range activation in T-cell lymphoma. The study identifies key limitations, such as the lack of analysis of c-myb neighboring genes and the potential for overexpression to become dispensable during outgrowth in vitro and tumor progression in vivo. The study suggests future research directions, such as the analysis of c-myb neighboring genes and the exploration of the role of c-myb in other types of hemopoietic tumors. The study also suggests the potential for the development of targeted therapies that specifically target c-myb in T-cell lymphoma and other hemopoietic tumors. The study highlights the importance of further research in this area to better understand the role of c-myb in hemopoietic tumors and to develop effective treatments for these diseases.