Human Molecular Genetics Advance Access originally published online on September 30, 2004
Human Molecular Genetics 2004 13(23):2925-2936; doi:10.1093/hmg/ddh315
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Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved
Disruption of a novel ectodermal neural cortex 1 antisense gene, ENC-1AS and identification of ENC-1 overexpression in hairy cell leukemia
1Department of Oncology/Pathology, CCK, Karolinska Hospital and Institute, Stockholm, Sweden, 2Department of Medicine, Division of Hematology, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden and 3Department of Hematology, University Hospital Groningen, Groningen, The Netherlands
Received June 24, 2004; Revised August 27, 2004; Accepted September 22, 2004
Karyotypical alteration of chromosome 5 and in particular band 5q13 is a frequent finding in hairy cell leukemia (HCL). We have previously identified a number of candidate genes localized in close proximity to a constitutional inv(5)(p13.1q13.3) breakpoint in one HCL patient. These included beta-hexosaminodase HEXB, frequently mutated in the lysosomal storage disorder Sandhoff disease. We now report that the 5q13.3 breakpoint disrupts a novel evolutionary conserved alternative isoform of HEXB. This isoform directly overlaps, in a cis-antisense fashion, exon 1 of the gene for ectodermal neuronal cortex 1 ENC-1, and was thus named ENC-1AS. ENC-1 has previously been shown to be overexpressed in several malignancies, and is believed to play a critical regulatory role in malignant transformation of various tumors. Importantly, subsequent analysis of ENC-1 in purified primary HCL tumor cells revealed a striking upregulation of ENC-1 in all 26 patients examined, compared with normal peripheral blood lymphocytes from healthy donors. Upon further analysis of the ENC-1/ENC-1AS locus, we identified a complex 5' regulatory mechanism involving an inverse expression of the ENC-1 sense and the ENC-1AS transcripts in several tissues supporting the hypothesis that expression of ENC-1AS regulates ENC-1 levels. In addition, we have also found tissue-specific methylation of a 1.2 kb segment encompassing the overlapping ENC-1/ENC-1AS 5' exons, adding to the complexity of the regulation of this locus. Altogether, these results suggest that upregulation of ENC-1 contributes to the development of HCL and provides new information on the possible dysregulation of ENC-1 including expression of a novel antisense gene, ENC-1AS.
* To whom correspondence should be addressed at: Department of Oncology/Pathology, CCK R8:03, 171 76, Karolinska Hospital, Stockholm, Sweden. Tel: +46 851773738; Fax: +46 8339031; Email: olle.sangfelt{at}cck.ki.se
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