A transcription map of the minimally deleted region from 13q14 in B-cell chronic lymphocytic leukemia as defined by large scale sequencing of the 650 kb critical region

Abstract

Extensive analysis of tumors has demonstrated homozygous and heterozygous deletions in chromosome region 13q14.3 in B-cell chronic lymphocytic leukemia (B-CLL), suggesting the site of a tumor suppressor gene. Since previous searches for this gene have not yielded any viable candidates, we now present the sequence of the BACs which span the minimally deleted approximately 650 kb region between markers D13S319 and D13S25. This sequence has allowed us to create the de®nitive transcription map for the region which reveals 93 ESTs and 12 Unigene clusters in this region. Using gene prediction programs, a further 19 potential genes are also identi®ed. The genes show an asymmetrical distribution throughout the region with most of them clustering at the extreme ends. This sequencing eort provides for the de®nitive structure of the B-CLL deletion region and the identi®cation of the vast majority of the potential candidate genes. Of all the genes identi®ed, only three have homologies to known genes: two L1 repeat genes and rabbit epididymal protein 52. This 13q14.3 sequence provides the ®nal substrate from which to characterize the B-CLL tumor suppressor gene.

WAVE3, an actin-polymerization gene, is truncated and inactivated as a result of a constitutional t(1;13)(q21;q12) chromosome translocation in a patient with ganglioneuroblastoma

“…High throughput genomic sequencing of BACs was performed as described by Kitamura et al (2000). Genomic sequences were analysed in blocs of 20 kb of sequence using the BLASTN program against the dbEST database (Altschul et al, 1990).…”

Integrated Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Subtypes of Deletion 13q14

“…Efforts by multiple groups have identified candidate genes within an f1 Mb stretch on chromosome 13 that have each been implicated in CLL del13q14 biology; nonetheless, mutations in these genes have not been identified and questions remain as to the validity of reducing the biology of del13q14 to a minimal deleted region or a single-gene mutation/expression event (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Analysis of del13q14 is further complicated by an evolving understanding of resident gene structure and the discovery of complex noncoding RNAs (20).…”

The 13q and 11q B‐cell chronic lymphocytic leukaemia‐associated regions derive from a common ancestral region in the zebrafish

“…Detailed deletion analyses of B-CLL samples have revealed a consensus region of approximately 790 kb on 13q14 between SETDB2 and D13S25 (Fig 1) (Kitamura et al, 2000;Bullrich et al, 2001;Mabuchi et al, 2001;Migliazza et al, 2001;Wolf et al, 2001). High-resolution contigs of this region have been generated independently by several groups and minimally deleted sub-regions have been defined (Kalachikov et al, 1997;Liu et al, 1997;Corcoran et al, 1998;Stilgenbauer et al, 1998).…”

“…Physical maps of the 13q14 and 11q22-23 larger commonly deleted regions, encompassing the critical minimal-deleted regions (MinDRs), were compiled from a combination of updated database of the human genome sequence (http:// www.ncbi.nlm.nih.gov/mapview), previous publications defining the deleted regions (Auer et al, 2001, Stilgenbauer et al, 1996Zhu et al, 1999;Kitamura et al, 2000;Bullrich et al, 2001;Mabuchi et al, 2001;Migliazza et al, 2001;Wolf et al, 2001) and our own 40 Mb 11q21-qter YAC/bacterial artificial chromosome and P1 artificial chromosome contig map (Tunnacliffe et al, 1999).…”

“…At 13q14, a consensus region of deletion with an approximate size of 600 kb between D13S273 and D13S25 has been described (Kitamura et al, 2000;Bullrich et al, 2001;Mabuchi et al, 2001;Migliazza et al, 2001;Wolf et al, 2001), although various reports have described smaller internal regions, based largely on the observations from one or two cases (Kalachikov et al, 1997;Liu et al, 1997;Corcoran et al, 1998;Stilgenbauer et al, 1998). Deletion and/or downregulation of microRNAs mir-15a and mir-16-1 at 13q14AE3 have also recently been proposed as important in B-CLL pathogenesis (Calin et al, 2002(Calin et al, , 2005a being repressors of the anti-apoptotic protein Bcl-2 (Cimmino et al, 2005).…”