Thomas Boehm

Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma.

Deletions affecting the interval between the RB1 gene and marker D13S25 at band 13q14 are the most frequent genetic abnormalities of B-cell chronic lymphocytic leukemia (B-CLL) and indicate the presence of a novel tumor suppressor gene in this region. In the current study, a high resolution physical map of fragments spanning one megabasepair (Mb) of genomic DNA at the critical 13q14 segment was constructed. To define the minimal region of loss within the RB1 and D13S25 interval, we screened 322 B-CLLs for deletions at either of the two loci. Thirty mantle cell lymphomas (MCLs) were included in the analysis because we observed a 13q14 deletion pattern similar to B-CLL in this disease. The incidence of 13q14 deletions was 51% in B-CLL and 70% in MCL, respectively. No frequent loss of the BRCA2 gene at band 13q12 was found. Detailed deletion mapping at band 13q14 with probes from the RB1–D13S25 interval lead to the identification of a critical deletion region 400 kb in size. Within this region two segments were most frequently affected, one at D13S272 120 kb in size and another 240 kb distal of D13S272 80 kb in size. From these two segments expressed sequences were identified as candidates for the putative 13q14 tumor suppressor gene involved in the pathogenesis of B-CLL and MCL.

Characterization of mouse and human nude genes.

Abstract The differentiation of primitive epithelial precursor cells in the thymic primordium into subcapsular, cortical, and medullary epithelial cells of the mature thymus requires the activity of the nude gene product Whn. Whn is also required for proper keratinization of the hair shaft. We determined the nucleotide sequence of a 58 kilobase region on mouse chromosome 11 that encompasses the mouse nude gene and part of the two neighboring genes, encoding a sodium/dicarboxylate co-transporter and the retinal protein 4. Using cross-hybridization, the human orthologue of the mouse nude gene was isolated. The human WHN protein also consists of 648 amino acids, 85% of which are identical to the mouse protein. Like the mouse gene, the human gene consists of eight coding exons and utilizes two alternative first exons in a tissue-specific fashion. Sequences upstream of the two alternative first exons display promoter activity in heterologous reporter assays. Whereas both promoters appear to be active in skin (albeit at different levels), only the most upstream element is active in the thymus, indicating that transcriptional activity of the whn gene is subject to complex regulation. Nucleotide sequence database comparisons reveal that among other winged-helix genes, the HTLF and HTLFL1 genes are most closely related to whn, although the exon/intron structure of the human HTLF gene in the DNA binding domain differs from that of whn.