Alterations of multiple tumor suppressor genes (p53 (17p13),p16INK4 (9p21), andDBM (13q14)) in B-CELL chronic lymphocytic leukemia

1995 ◽  
Vol 14 (3) ◽  
pp. 141-146 ◽  
Author(s):  
Elizabeth W. Newcomb ◽  
Laxmi S. Rao ◽  
Sonia S. Giknavorian ◽  
Seung Y. Lee
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Genes ◽  
Lymphocytic Leukemia ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
Cell Chronic Lymphocytic Leukemia

scholarly journals Minimal region of loss at 13q14 in B-cell chronic lymphocytic leukemia

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 3109-3115 ◽  
Author(s):  
F Bullrich ◽  
ML Veronese ◽  
S Kitada ◽  
J Jurlander ◽  
MA Caligiuri ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Genes ◽  
Lymphocytic Leukemia ◽  
Allelic Loss ◽  
Loss Of Function ◽  
Suppressor Genes ◽  
Chromosome 13 ◽  
Cell Chronic Lymphocytic Leukemia

Allelic loss at nonrandom chromosomal sites is thought to mark the position of tumor suppressor genes involved in the pathogenesis and progression of human malignancies. Solid tumors in particular have been found to harbor multiple genetic changes resulting in loss of function mutations. Tumor suppressor genes have also been found to be involved in the progression of lymphoid tumors. Previous reports have suggested the involvement of a tumor suppressor gene located on the long arm of chromosome 13, between the retinoblastoma (RB) and D13S25 loci, in the pathogenesis and or progression of more than 40% of B-cell chronic lymphocytic leukemia (B-CLL), a common lymphoid malignancy whose molecular etiology remains largely unknown. In the present study, we report the construction and characterization of a YAC contig spanning a region of approximately 3 cM between the RB gene and the D13S31 locus. We also screened 60 paired normal/tumor B-CLL samples for allelic loss on chromosome 13 with nine microsatellite markers located between RB and D13S25. This analysis has allowed us to narrow the smallest region of loss to a segment of 550 kb located between the 206XF12 and D13S25 markers.

The 13q and 11q B-Cell Chronic Lymphocytic Leukemia Deleted Regions Derive from a Common Ancestral Region in the Zebrafish on Linkage Group 9.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 295-295
Author(s):  
Rebecca L. Auer ◽  
Sophia Riaz ◽  
Finbarr E. Cotter
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Linkage Group ◽  
Human Chromosome ◽  
B Cell ◽  
Critical Region ◽  
Tumor Suppressor Genes ◽  
Zebrafish Genome ◽  
Lymphocytic Leukemia ◽  
Human Chromosomes ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Loss of the long arm of chromosomes 11 and 13 are the most consistent cytogenetic abnormalities for patients with B-cell chronic lymphocytic leukemia (B-CLL). They suggest the presence of as yet unidentified tumor suppressor genes within well defined minimal deleted regions (MDRs). The use of small vertebrate organisms, such as the zebrafish, as models of diseases associated with chromosomal deletions enables the functional analysis of potential causative genes. Hemopoiesis is well conserved between the zebrafish and human and conserved synteny exists between the two genomes. In this study, the evolutionary conservation between the zebrafish and human genome is investigated for the 13q14 and 11q22-23 regions deleted in B-CLL. Zebrafish orthologs have been identified and radiation hybrid (RH) mapping performed to confirm their chromosomal location and define regions of conserved synteny.We have identified 38 zebrafish orthologs of the human genes in the MDRs in zebrafish cDNA and the syntenic regions for the human deletions in the zebrafish genome. The 13q14 region was syntenic with two main regions in the zebrafish genome, namely linkage group 1 (LG1) and LG9. The majority of zebrafish orthologs to 11q22-23 were found on LG5, LG15 and LG21. One syntenic region, LG9, in the zebrafish genome is of potential interest. Analysis of the smallest critical region of deletion in B-CLL for both 11q22-23 and 13q14 reveals that the human gene equivalents are contained within an area of 22.02 cR on LG9 (approximately 3260 kb). Within LG9, orthologs to two genes to human chromosome 11, three to human chromosome 13 and two chromosome 13 microRNAs (mir-15a and mir-16-1) were identified. The critical region on zebrafish LG9 maps to the MDR for both human chromosomes, suggesting a common ancestry for the B-CLL tumor suppressor genes. This is further supported by analysis of the chicken genome where the same 5 genes from 13q14 and 11q22-23 (C13orf1, RFP2, FLJ11712, FDX1, ARHGAP20) lie within a 10.04 Mb region on chromosome 1. In addition, TILLING for knock-outs of genes in this region of zebrafish embryos will allow analysis of their in vivo potential for lymphoproliferation and may define prime causative genes for B-CLL within human chromosomes 11q and 13q by reverse genetics. Our study provides an explanation for involvement of both 11q and 13q in B-CLL and the potential to develop animal models for this common lymphoproliferative disorder.

scholarly journals Differential genome-wide array–based methylation profiles in prognostic subsets of chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 296-305 ◽  
Author(s):  
Meena Kanduri ◽  
Nicola Cahill ◽  
Hanna Göransson ◽  
Camilla Enström ◽  
Fergus Ryan ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Lymphocytic Leukemia ◽  
Chain Reaction ◽  
Global Methylation ◽  
Suppressor Genes ◽  
Genome Wide ◽  
Polymerase Chain

Abstract Global hypomethylation and regional hypermethylation are well-known epigenetic features of cancer; however, in chronic lymphocytic leukemia (CLL), studies on genome-wide epigenetic modifications are limited. Here, we analyzed the global methylation profiles in CLL, by applying high-resolution methylation microarrays (27 578 CpG sites) to 23 CLL samples, belonging to the immunoglobulin heavy-chain variable (IGHV) mutated (favorable) and IGHV unmutated/IGHV3-21 (poor-prognostic) subsets. Overall, results demonstrated significant differences in methylation patterns between these subgroups. Specifically, in IGHV unmutated CLL, we identified methylation of 7 known or candidate tumor suppressor genes (eg, VHL, ABI3, and IGSF4) as well as 8 unmethylated genes involved in cell proliferation and tumor progression (eg, ADORA3 and PRF1 enhancing the nuclear factor-κB and mitogen-activated protein kinase pathways, respectively). In contrast, these latter genes were silenced by methylation in IGHV mutated patients. The array data were validated for selected genes using methylation-specific polymerase chain reaction, quantitative reverse transcriptase–polymerase chain reaction, and bisulfite sequencing. Finally, the significance of DNA methylation in regulating gene promoters was shown by reinducing 4 methylated tumor suppressor genes (eg, VHL and ABI3) in IGHV unmutated samples using the methyl-inhibitor 5-aza-2′-deoxycytidine. Taken together, our data for the first time reveal differences in global methylation profiles between prognostic subsets of CLL, which may unfold epigenetic silencing mechanisms involved in CLL pathogenesis.

Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 2098-2104 ◽  
Author(s):  
Anna Migliazza ◽  
Francesc Bosch ◽  
Hirokazu Komatsu ◽  
Eftihia Cayanis ◽  
Stefano Martinotti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Lymphocytic Leukemia ◽  
Allelic Loss ◽  
Computer Assisted ◽  
Putative Tumor Suppressor Gene ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Deletions of the 13q14 chromosome region are associated with B-cell chronic lymphocytic leukemia (B-CLL) and several other types of cancer, suggesting the presence of a tumor suppressor gene. In previous studies the minimal region of deletion (MDR) was mapped to a less than 300-kilobase (kb) interval bordered by the markers 173a12-82 and 138G4/1.3R. For the identification of the putative tumor suppressor gene, the entire MDR (approximately 347 kb) has been sequenced, and transcribed regions have been identified by exon trapping, EST-based full-length complementary DNA cloning, database homology searches, and computer-assisted gene prediction analyses. The MDR contains 2 pseudogenes and 3 transcribed genes: CAR, encoding a putative RING-finger containing protein; 1B4/Leu2, generating noncoding transcripts; and EST70/Leu1, probably representing another noncoding gene (longest open reading frame of 78 codons). These genes have been sequenced in 20 B-CLL cases with 13q14 hemizygous deletion, and no mutations were found. Moreover, no somatic variants were found in the entire MDR analyzed for nucleotide substitutions by a combination of direct sequencing and fluorescence-assisted mismatch analysis in 5 B-CLL cases displaying 13q14-monoallelic deletion. The nondeleted allele of theCAR and EST70/Leu1 genes was expressed in B-CLL specimens, including those with monoallelic loss, whereas no expression of 1B4/Leu2 was detectable in B-CLL, regardless of the 13q14 status. These results indicate that allelic loss and mutation of a gene within the MDR is an unlikely pathogenetic mechanism for B-CLL. However, haplo-insufficiency of one of the identified genes may contribute to tumorigenesis.

Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4116-4121 ◽  
Author(s):  
Daniel Mertens ◽  
Stephan Wolf ◽  
Petra Schroeter ◽  
Claudia Schaffner ◽  
Hartmut Döhner ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Suppressor ◽  
B Cell ◽  
Quantitative Polymerase Chain Reaction ◽  
Lymphocytic Leukemia ◽  
Chromosome Band ◽  
Chromosomal Band ◽  
Down Regulation ◽  
Cell Chronic Lymphocytic Leukemia

Loss of genomic material from chromosomal band 13q14.3 is the most common genetic imbalance in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma, pointing to the involvement of this region in a tumor suppressor mechanism. From the minimally deleted region, 3 candidate genes have been isolated, RFP2, BCMS, and BCMSUN. DNA sequence analyses have failed to detect small mutations in any of these genes, suggesting a different pathomechanism, most likely haploinsufficiency. We, therefore, tested B-CLL patients for epigenetic aberrations by measuring expression of genes from 13q14.3 and methylation of their promotor region.RB1, CLLD7, KPNA3, CLLD6, andRFP2 were down-regulated in B-CLL patients as compared with B cells of healthy donors, with RFP2 showing the most pronounced loss of expression. To test whether this loss of gene expression is associated with methylation of CpG islands in the respective promotor regions, we performed methylation-sensitive quantitative polymerase chain reaction analyses and bisulfite sequencing on DNA from B-CLL patients. No difference in the methylation patterns could be detected in any CpG island of the minimally deleted region. Down-regulation of genes within chromosomal band 13q14.3 in B-CLL is in line with the concept of haploinsufficiency, but this tumor-specific phenomenon is not associated with DNA methylation.

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