Human Molecular Genetics Advance Access published online on September 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh315
© 2004 by Oxford University Press
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1 Department of Oncology/Pathology, CCK, Karolinska Hospital and Institute, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: olle.sangfelt{at}cck.ki.se.
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 to 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.
Article
Disruption of a novel Ectodermal Neural Cortex 1 antisense gene, ENC-1AS and identification of ENC-1 overexpression in hairy cell leukemia
2 Department of Medicine, Division of Hematology, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden
3 Department of Hematology, University Hospital Groningen, Groningen, The Netherlands
4 Department of Oncology/Pathology, CCK R8:03, 171 76, Karolinska Hospital, Stockholm, Sweden
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