Minimal truncation of the c-myb gene product in rapid-onset B-cell lymphoma

Abstract

Oncogenic activation of c-myb by insertional mutagenesis has been implicated in rapid-onset B-cell lymphomas induced by the nonacute avian leukosis virus EU-8. In these tumors, proviruses are integrated either upstream of the c-myb coding region or within the first intron of c-myb. Tumors with either type of integration contained identical chimeric mRNAs in which the viral 5 splice site was juxtaposed to the 3 splice site of c-myb exon 2 and myb exon 1 was eliminated. Both classes of integrations generated truncated Myb proteins that were indistinguishable by Western analysis. In contrast to most other examples of c-myb activation, the truncation consisted of only 20 N-terminal amino acids and did not disrupt either the DNA binding domain near the N terminus or the negative regulatory domain near the C terminus of Myb. The significance of the 20-amino-acid Myb truncation to tumorigenesis was tested by infection of chicken embryos with retroviral vectors expressing different myb gene products. While virus expressing either wild-type c-myb or c-myb mutated at the N-terminal casein kinase II sites was only weakly oncogenic at 10 weeks, the minimally truncated myb virus induced a high incidence of rapid-onset tumors, including B-cell lymphomas, sarcomas, and adenocarcinomas.

N-Terminal Truncated Myb with New Transcriptional Activity Produced Through Use of an Alternative MYB Promoter in Salivary Gland Adenoid Cystic Carcinoma

“…The N-terminal region of Myb is highly conserved, indicating an important function. Early studies implicated N-terminal truncation in oncogenesis, a mere 20 amino acid N-terminal truncation was sufficient to induce rapid-onset tumors when expressed in chickens [52]. While, phosphorylation of the pS11 and pS12 residues increased the specificity of full-length Myb by destabilizing DNA-binding [33,53], this effect was overcome by protein-to-protein interactions with co-factors that anchored Myb to DNA [33].…”

Pushing the limits of the scanning mechanism for initiation of translation

“…1B) support the interpretation that an AUG codon which follows the upORF too closely is skipped (presumably because ribosomes have not yet reacquired Met-tRNA i ), allowing reinitiation to occur farther downstream. The same mechanism might be invoked to explain how an internal start codon is accessed in miniTrpRS mRNA (Wakasugi et al, 2002) and baculovirus IE0 mRNA (Theilmann et al, 2001), and how c-myb gets translated from a rearranged transcript generated by retrovirus insertion (Jiang et al, 1997). In each of these mRNAs, the first AUG codon that follows a small upORF must be bypassed to reach the functional start codon downstream.…”

Identification of Protein Instability Determinants in the Carboxy-Terminal Region of c-Myb Removed as a Result of Retroviral Integration in Murine Monocytic Leukemias

“…Promoter insertion is not the only mechanism involved in the activation of c-myb by retroviruses. Amino-terminal truncations occur in every case when the retrovirus inserts its promoter at the 5Ј end of the gene, and although the role of this truncation in murine myeloid leukemia is not clear and may be a consequence of bypassing the elongation block, removal of similar sequences at the N terminus of avian c-Myb causes it to be more oncogenic in its induction of B-cell lymphomas (12). Recently, we have been focusing on a set of leukemias that have carboxy-terminal truncations due to virus integration into the central part of the locus, in the absence of promoter insertion.…”