Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Abstract

Genomic material from chromosome band 13q14.3 distal to the retinoblastoma locus is recurrently lost in a variety of human neoplasms, indicating an as-yet-unidentified tumor-suppressor mechanism. No pathogenic mutations have been found in the minimally deleted region until now. However, in B cell chronic lymphocytic leukemia tumors with loss of one copy of the critical region, respective candidate tumor-suppressor genes are downregulated by a factor >2, which would be expected by a normal gene-dosage effect. This finding points to an epigenetic pathomechanism. We find that the two copies of the critical region replicate asynchronously, suggesting differential chromatin packaging of the two copies of 13q14.3. Although we also detect monoallelic silencing of genes localized in the critical region, monoallelic expression originates from either the maternal or paternal copy, excluding an imprinting mechanism. DNA methylation analyses revealed one CpG island of the region to be methylated. DNA demethylation of this CpG island and global histone hyperacetylation induced biallelic expression, whereas replication timing was not affected. We propose that differential replication timing represents an early epigenetic mark that distinguishes the two copies of 13q14.3, resulting in differential chromatin packaging and monoallelic expression. Accordingly, deletion of the single active copy of 13q14.3 results in significant downregulation of the candidate genes and loss of function, providing a model for the interaction of genetic lesions and epigenetic silencing at 13q14.3 in B cell chronic lymphocytic leukemia.DNA methylation ͉ monoallelic expression ͉ replication timing

Genomic aberrations in mantle cell lymphoma detected by interphase fluorescence in situ hybridization. Incidence and clinicopathological correlations

“…17 Interestingly, in MCL biallelic deletions were only detected in 7% of 13q14 deleted cases, a finding contrasting with the incidence of 24% in CLL. 26 This might point to an epigenetic pathomechanism similar to that recently described in CLL 35 by which the deletion of the single active copy of 13q14.3 might result in significant down-regulation of the candidate genes. However, while in CLL genomic material from chromosome band 13q14.3 is lost distal to the retinoblastoma gene (RB), in some MCL cases RB might also be a potential candidate.…”

Nucleoside analogs: molecular mechanisms signaling cell death

“…For instance, CpG island methylation leads to the silencing of miR-127 expression, leading to the enhanced expression of Bcl-6, a proto-oncogene linked to non-Hodgkin's lymphoma (Saito et al, 2006). Epigenetic silencing of miR15a and 16-1, miRs that target Bcl-2, were found in B-CLL (Mertens et al, 2006). Aberrant hypermethylation of miR-9-1, miR124a, miR-148, miR-152 and miR-663 is an early event in breast cancer (de Klein et al, 2000).…”

“…Other reports have demonstrated hypermethylation-induced silencing of miR-203 leading to overexpression of oncogenic BcrAbl in chronic myelogenous leukemia (Bueno et al, 2008). Consequently, exposure to decitabine, alone or in combination with histone deacetylase inhibitors restores miRNA expression with corresponding declines in target oncogene expression and apoptosis of neoplastic cells (Calin and Croce, 2006;Mertens et al, 2006;Saito et al, 2006;Zhang et al, 2008). Therefore, as methylation patterns that affect miRNA expression become better understood, opportunities may arise that support the use of select nucleoside analogs to target specific gene expression.…”

Chronic lymphocytic leukemia - genomics lead the way

“…17 Similarly, in 13q14, the region that is most commonly genetically inactivated, we have identified a complex epigenetic tumor suppressor mechanism. 18 It is, therefore, possible that a similar sequence of events at 13q14 leads to the development of CLL: first a gradual epigenetic silencing of a tumor suppressor mechanism which is then superseded by full genetic inactivation by deletion (Figure 1). 19 An initial epigenetic aberration predisposing to CLL could also explain the surprising recent finding that hematopoietic stem cells isolated from CLL patients are capable of forming a transplantable CLL precursor-like disease in mice, suggesting a common aberration already present in the hematopoietic stem cells ( Figure 1A).…”