Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification.

Although the neoplastic significance of the chromosome changes widespread in Hodgkin's disease (HD) remains obscure, a distinct cytogenetic picture has emerged combining aneuploidy with structural rearrangements clustered at certain breakpoints. Notably absent are the recurrent chromosome translocations which distinguish other hematopoietic neoplasms and serve as clues to underlying oncogene alterations. The paucity of neoplastic cells in HD biopsies hinders detailed chromosome analysis. As an alternative, we investigated a panel of well characterized cell lines by classical and molecular cytogenetics, using single-gene and subtelomeric probes, including three autologous HD examples (HDLM-1/2/3) analyzed by 'spectral karyotyping' - the first complete HD karyotype to be documented. Although complex, most rearrangements in HDLM cells arose in vivo and included few rare but many typical HD breakpoints, notably at the r(ibosomal)DNA regions. Two types of genomic rearrangement involving DNA repeats were conspicuous: insertion and genomic amplification/coamplification of rDNA-the first genomic rDNA rearrangements to be reported in a tumor cell, and the first example of multiple 'jumping translocations' (JT). Of four subtelomeric microsatellite repeats tested in HDLM cells, three exhibited interstitial sites at JT, of which two (at 5qter and 9pter) were respectively associated with deletion of the 5q31-32 myeloid region, and coamplification of a recently described HD-recurrent amplicon at 9p2 together with transcriptionally silent rDNA. Altogether, three out of four HD cell lines carried interstitial 9p subtelomeres and rDNA rearrangements. Taken together, these data suggest tumorigenic rearrangements may be facilitated by 'hitchhiking' along with mobile DNA repeat sequences which may target gene rearrangement at 9p in HD. Southern analysis of parallel rearrangements within rDNA intergenic spacers in HDLM cells highlighted several at, or near, retroposons. As well as validating HD cell lines as cytogenetic models, and resources for identifying genes rearranged in HD, our findings warrant further investigation of the roles of DNA repeat sequences, notably subtelomeric microsatellites, rDNA spacer sequences and retroposons as facilitators and markers of tumor-gene rearrangement.