Disruption of the Hexb/Enc-1 Antisense Gene and Identification of Elevated Enc-1 Expression in Patients with Hairy Cell Leukemia.

Chromosomal aberrations on chromosome 5 and in particular band 5q13 is frequently seen in Hairy Cell Leukemia (HCL). Detailed characterization of a constitutional inv (5)(p13.1q13.3) breakpoint in one HCL patient yielded a number of candidate genes that might be important for the development of this malignancy. One of these was beta-hexosaminodase, HEXB, commonly mutated in the lysosomal storage disorder Sandhoff disease. The 5q13.3 breakpoint disrupts a novel evolutionarily conserved alternative isoform of HEXB. This isoform directly overlaps, in a cis-antisense fashion, the first exon of the gene for ectodermal neuronal cortex 1, ENC-1, and was thus named ENC-1AS. The ENC-1 gene has previously been shown to be overexpressed in a variety of malignancies and has been described as a potential oncogene. Analysis of ENC-1 in purified primary HCL tumor cells showed marked upregulation of ENC-1 expression in all patients examined, compared to normal peripheral blood lymphocytes from healthy donors. Although initially found as a p53-induced gene, the upregulation of ENC-1 in HCL follows a p53-independent pathway since activation of the p53 pathway did not lead to further increase in ENC-1 expression in HCL cells. Examining the ENC-1/ENC-1AS locus in more detail, we identified a complex regulatory mechanism involving an inverse expression of the ENC-1 sense and the ENC-1AS transcripts in several tissues. Thus, it appears as if upregulation of ENC-1 is a common phenomenon in HCL and that the regulation of this gene may be dependent on its novel antisense partner ENC-1AS.