Activation of c- myb by 5′ retrovirus promoter insertion in myeloid neoplasms is dependent upon an intact alternative splice donor site (SD′) in gag

Alternative splicing in Mo-MuLV recruits a splice donor site, SD′, within the gag that is required for optimal replication in vitro. Remarkably, this SD′ site was also found to be utilized for production of oncogenic gag-myb fusion RNA in 100% of murine-induced myeloid leukemia (MML) in pristane-treated BALB/c mice. Therefore, we investigated the influence of silent mutations of SD′ in this model. Although there was no decrease in the overall incidence of disease, there was a decrease in the incidence of myeloid leukemia with a concomitant increase in lymphoid leukemia. Importantly, there was a complete lack of myeloid tumors associated with 5′ insertional mutagenic activation of c- myb, suggesting the specific requirement of the SD′ site in this mechanism.