DLEU2, Located within the CLL 13q14 Deletion Locus, Encodes an Antisense RNA for the Putative Bicistronic RFP2/LEU5 Gene in Humans and Mouse.

Abstract

Our group previously identified two novel genes, RFP2/LEU5 and DLEU2, within a 13q14.3 genomic region of loss seen in various malignancies, including chronic lymphocytic leukemia and mantle cell lymphoma. However, no specific inactivating mutations were found in these or other genes in the vicinity of the deletion, strongly suggesting that a nonclassical tumor-suppressor mechanism may be involved. Our recent analysis demonstrates that the DLEU2 gene encodes a putative noncoding antisense RNA, with one exon directly overlapping the first exon of the RFP2/LEU5 gene in the opposite orientation. In addition, the RFP2/LEU5 transcript can be alternatively spliced to produce either several monocistronic transcripts or a putative bicistronic transcript encoding two separate open-reading frames, adding to the complexity of the locus. The finding that these gene structures are conserved in mouse, including the putative bicistronic RFP2/LEU5 transcript as well as the antisense relationship with DLEU2, further underlines the significance of this unusual organization and suggests a biological function for DLEU2 in the regulation of RFP2/LEU5. Further characterisation of the 13q14 deletion locus distal to the RFP2/DLEU2 region has resulted in the identification of two novel evolutionary conserved genes DLEU7 and DLEU8, the latter of which may function as both a protein encoding and an cis-antisense gene. The combined data indicates that the CLL 13q14 deletion locus encompasses a highly complex gene regulatory system, the partial deletion of which may affect the post-transcriptional regulation of non-deleted genes in the vicinity.