Genomic instability during Myc-induced lymphomagenesis in the bursa of Fabricius

Abstract

Retroviral vector-mediated overexpression of c-myc in embryonic bursal precursors induces multi-staged tumorigenesis beginning with preneoplastic-transformed follicles (TF) and progressing to clonal metastatic B-cell lymphomas. Using a 13K chicken cDNA microarray, specifically enriched for chicken immune system expressed sequence tagged (ESTs), we carried out array-based comparative genomic hybridization (array-CGH) and detected significant DNA copy number change at many loci on most or all chromosomes in both early TF and end-stage lymphomas. Formation of long palindromes, through breakage-fusion-bridge cycles, is thought to play an early role in gene amplification. Employing genome-wide analysis of palindrome formation (GAPF), we detected extensive palindrome formation in early TF and end-stage lymphomas. The population of loci showing amplification by array-CGH was enriched for palindromes detected by GAPF providing strong evidence for genetic instability early in Myc-induced tumorigenesis and further support for the role of palindromes in gene amplification. Comparing gene copy number change and RNA expression changes profiled on the same cDNA array, we detected very little consistent contribution of gene copy number change to RNA expression changes. Palindromic loci in TF and tumors, however, were expressed, many at high levels, suggesting an abundance of RNA species with long double-stranded segments generated during tumorigenesis.

Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

“…This model implies that revertant tetraploid-diploid cells are inherently different from the starting diploid population in a manner that escapes detection by crude assessments of ploidy such as flow cytometry. The additional ability of GpIba to induce nuclear and chromatin abnormalities and DSBs (Figures 4i and 5a), as well as other possible genomic abnormalities attributable to c-Myc overexpression (Neiman et al, 2006;Prochownik and Li, 2007) is also consistent with this model. While the relative contribution of each form of DNA damage is unknown, clear relationships exist among defects in DSB repair, cell cycle checkpoints and aneuploidy (Iarmarcovai et al, 2006).…”

c-Myc: Linking Transformation and Genomic Instability

“…Continued over-expression of c-Myc produced more profound rearrangements such as whole chromosome breaks, fusions and the accumulation of extrachromosomal elements [83]. More recently, a genome-wide analysis of DNA copy number changes in c-Myc over-expressing chicken bursal cells as they progress from pre-neoplastic transformed follicles to metastatic cancers showed widespread palindrome formation, although this did not necessarily correlate with changes in gene expression [84]. Palindromic repeats, however, do suggest the existence of many mRNAs with long segments of double-stranded structure.…”

c-MYC-Induced Genomic Instability

“…Recent reviews have addressed this role of MYC in instability (Dang et al 2005;Prochownik and Li 2007;Prochownik 2008). Also, genome-wide approaches have highlighted MYC's overall potential to impact the genomic stability of the cell (Neiman et al 2006(Neiman et al , 2008. However, once instability is present, MYC does not always promote additional genomic instability (Gao et al 2007).…”