Alternative titles; symbols
ORPHA: 67038; DO: 1040;
Cytogenetic location: 13q14 Genomic coordinates (GRCh38): 13:39,500,001-54,700,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14 | {Leukemia, chronic lymphocytic, susceptibility to, 2} | 109543 | Autosomal dominant | 2 |
For a phenotypic description and a discussion of genetic heterogeneity of chronic lymphocytic leukemia (CLL), see 151400.
Roughly 25% of human B-cell chronic lymphocytic leukemias are characterized by a chromosomal lesion involving 13q14. Brown et al. (1993) found that in all except 1 of 11 cases of low-grade B-cell malignancy, with deletions or translocations involving 13q14, the change was in the region of D13S25, with at least 4 cases showing homozygous disruption. They concluded that D13S25 lies close to a tumor suppressor locus whose inactivation contributes to the initiation or progression of low-grade B-cell malignancy. They showed that this locus is at least 530 kb telomeric to RB1. Involvement of RB1 (614041) in CLL could be excluded. They designated the new locus DBM, for 'disrupted in B-cell malignancy.'
Toward the identification of the putative CLL tumor suppressor gene that resides in the 13q14 region, Kalachikov et al. (1997) constructed a high-resolution physical map of YAC, PAC, and cosmid contigs covering 600 kb of the 13q14 genomic region. In addition to densely positioned genetic markers and STSs, they further annotated the map by localization of 32 transcribed sequences (ESTs) using a combination of exon trapping, direct cDNA selection, sample sequencing of cosmids and PACs, and homology searches. On the basis of these mapping data, allelic loss analyses at 13q14 using CLL tumor samples allowed narrowing of the genomic segment encompassing the putative CLL gene to less than 300 kb. Within the minimally deleted region, there were 23 ESTs representing candidate exons for the CLL-associated tumor suppressor gene.
Variation in either the ARL11 (609351) or the MIRN16-1 (609704) gene, both of which map to chromosome 13q14.3, has been reported in patients with CLL.
Fabbri et al. (2011) found that CLL cells with a chromosome 13q14 deletion had significantly lower expression of MIRN16-1 and MIRN15A (609703) and significantly higher expression of TP53 (191170) than CLL cells with normal cytogenetic profiles. Studies in a megakaryocyte leukemia cell line (MEG-01) showed that overexpression of both these miRNAs resulted in decreased TP53 expression via direct binding. Downstream effectors of TP53, including BCL2 (151430), CDKN1A (116899), and BBC3 (605854), were also affected. In addition, TP53 directly stimulated the transcription of the miRNAs, consistent with a feedback loop. The higher levels of TP53 in these cells may keep the increase in tumor burden relatively low, which correlates with the observed indolent course in patients with chromosome 13q14 deletions. Involvement of TP53 with MIRN34B (611374) and MIRN34C (611375) in a feedback loop was also observed in CLL cells with a chromosome 11q23 deletion (612559). Moreover, changes in 1 family of miRNAs indirectly affected the expression of the other family of miRNAs by modulating the levels of TP53. Fabbri et al. (2011) concluded that their findings indicated that a microRNA/TP53 feedback circuit is associated with the pathogenesis and prognosis of CLL.
Brown, A. G., Ross, F. M., Dunne, E. M., Steel, C. M., Weir-Thompson, E. M. Evidence for a new tumour suppressor locus (DBM) in human B-cell neoplasia telomeric to the retinoblastoma gene. Nature Genet. 3: 67-72, 1993. [PubMed: 8490658] [Full Text: https://doi.org/10.1038/ng0193-67]
Fabbri, M., Bottoni, A., Shimizu, M., Spizzo, R., Nicoloso, M. S., Rossi, S., Barbarotto, E., Cimmino, A., Adair, B., Wojcik, S. E., Valeri, N., Calore, F., and 17 others. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA 305: 59-67, 2011. [PubMed: 21205967] [Full Text: https://doi.org/10.1001/jama.2010.1919]
Kalachikov, S., Migliazza, A., Cayanis, E., Fracchiolla, N. S., Bonaldo, M. F., Lawton, L., Jelenc, P., Ye, X., Qu, X., Chien, M., Hauptschein, R., Gaidano, G., Vitolo, U., Saglio, G., Resegotti, L., Brodjansky, V., Yankovsky, N., Zhang, P., Soares, M. B., Russo, J., Edelman, I. S., Efstratiadis, A., Dalla-Favera, R., Fischer, S. G. Cloning and gene mapping of the chromosome 13q14 region deleted in chronic lymphocytic leukemia. Genomics 42: 369-377, 1997. [PubMed: 9205107] [Full Text: https://doi.org/10.1006/geno.1997.4747]