Identification of novel Bach2 transcripts and protein isoforms through tagging analysis of retroviral integrations in...

The Bach2 gene functions as a transcriptional repressor in B-cells, showing high expression level only before the plasma cell stage. Several lines of evidence indicate that Bach2 is a B-cell specific tumor suppressor. We here address patterns of insertional mutagenesis and expression of Bach2 is a murine retroviral model of B-cell lymphoma induction.

We report that the Bach2 gene is a target of proviral integrations in B-cell lymphomas induced by murine leukemia virus. An alternative Bach2 promoter was identified within intron 2 and this promoter was activated in one of the tumors harboring proviral integration. The alternative promoter was active in both normal and tumor tissue and the tissue specificity of the two Bach2 promoters was similar. Three different alternatively used Bach2 terminal exons were identified to be located in intron 4. The inclusion of these exons resulted in the generation of Bach2 mRNA with open reading frames lacking the bZIP DNA binding domain present in the normal Bach2 protein, but retaining a partial BTB protein dimerization domain. Such Bach2 protein was excluded from the cell nucleus.

We have identified an alternative promoter and new protein isoforms of Bach2. Our data imply that activation of an alternative promoter by proviral integration serves as a possible mechanism of up-regulation of the Bach2 gene with a potential role in B-cell lymphomagenesis. The finding of novel Bach2 transcripts and protein isoforms will facilitate a better insight into the normal and pathophysiological regulation of the Bach2 gene.