title: Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles.
abstract: BACKGROUND
  Hodgkin's lymphoma is characterized by the presence of mono-nucleated Hodgkin cells and bi- to multi-nucleated Reed-Sternberg cells. We have recently shown telomere dysfunction and aberrant synchronous/asynchronous cell divisions during the transition of Hodgkin cells to Reed-Sternberg cells.1
  
  
  METHODS
  To determine whether overall changes in nuclear architecture affect genomic instability during the transition of Hodgkin cells to Reed-Sternberg cells, we investigated the nuclear organization of chromosomes in these cells.
  
  
  RESULTS
  Three-dimensional fluorescent in situ hybridization revealed irregular nuclear positioning of individual chromosomes in Hodgkin cells and, more so, in Reed-Sternberg cells. We characterized an increasingly unequal distribution of chromosomes as mono-nucleated cells became multi-nucleated cells, some of which also contained chromosome-poor 'ghost' cell nuclei. Measurements of nuclear chromosome positions suggested chromosome overlaps in both types of cells. Spectral karyotyping then revealed both aneuploidy and complex chromosomal rearrangements: multiple breakage-bridge-fusion cycles were at the origin of the multiple rearranged chromosomes. This conclusion was challenged by super resolution three-dimensional structured illumination imaging of Hodgkin and Reed-Sternberg nuclei. Three-dimensional super resolution microscopy data documented inter-nuclear DNA bridges in multi-nucleated cells but not in mono-nucleated cells. These bridges consisted of chromatids and chromosomes shared by two Reed-Sternberg nuclei. The complexity of chromosomal rearrangements increased as Hodgkin cells developed into multi-nucleated cells, thus indicating tumor progression and evolution in Hodgkin's lymphoma, with Reed-Sternberg cells representing the highest complexity in chromosomal rearrangements in this disease.
  
  
  CONCLUSIONS
  This is the first study to demonstrate nuclear remodeling and associated genomic instability leading to the generation of Reed-Sternberg cells of Hodgkin's lymphoma. We defined nuclear remodeling as a key feature of Hodgkin's lymphoma, highlighting the relevance of nuclear architecture in cancer.
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, CancerCare Manitoba, Winnipeg, MB, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Guffei
authors.forename: Rahul
authors.initials: R
authors.lastname: Sarkar
authors.forename: Ludger
authors.initials: L
authors.lastname: Klewes
authors.forename: Christiaan
authors.initials: C
authors.lastname: Righolt
authors.forename: Hans
authors.initials: H
authors.lastname: Knecht
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D016539:Reed-Sternberg Cells / Q000378:metabolism / Q000473:pathology; D032681:Spectral Karyotyping / Q000379:methods; D014178:Translocation, Genetic
references.citation: Curr Opin Cell Biol. 2006 Jun;18(3):307-16
references.pmid: 16687245
references.citation: Environ Mol Mutagen. 2009 Oct;50(8):741-7
references.pmid: 19326465
references.citation: Int J Cancer. 2002 Jun 10;99(5):665-72
references.pmid: 12115499
references.citation: Leukemia. 2000 Oct;14(10):1803-14
references.pmid: 11021756
references.citation: J Microsc. 2001 Nov;204(Pt 2):99-107
references.pmid: 11737543
references.citation: J Natl Cancer Inst. 2004 Feb 18;96(4):305-15
references.pmid: 14970279
references.citation: EMBO J. 2009 Sep 2;28(17):2532-40
references.pmid: 19629041
references.citation: Cytogenet Genome Res. 2007;116(1-2):1-11
references.pmid: 17268171
references.citation: Cancer Res. 1998 Sep 1;58(17):3974-85
references.pmid: 9731511
references.citation: J Exp Med. 1999 Jun 21;189(12):1939-46
references.pmid: 10377189
references.citation: J Cell Sci. 2008 Jun 1;121(11):1876-86
references.pmid: 18477608
references.citation: Blood. 2002 Jun 15;99(12):4283-97
references.pmid: 12036854
references.citation: Nat Rev Genet. 2007 Feb;8(2):104-15
references.pmid: 17230197
references.citation: Chromosoma. 2006 Dec;115(6):459-67
references.pmid: 16897100
references.citation: J Cell Biochem. 2010 Apr 15;109(6):1095-102
references.pmid: 20127711
references.citation: Proc Natl Acad Sci U S A. 1942 Nov;28(11):458-63
references.pmid: 16578057
references.citation: Nat Rev Cancer. 2009 Jan;9(1):15-27
references.pmid: 19078975
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5541-6
references.pmid: 15809428
references.citation: Oncogene. 2003 Apr 3;22(13):1978-87
references.pmid: 12673203
references.citation: Leukemia. 2009 Mar;23(3):565-73
references.pmid: 19039323
references.citation: Semin Cancer Biol. 2007 Feb;17(1):1-4
references.pmid: 17158061
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9613-8
references.pmid: 15983382
references.citation: Bioessays. 2004 Nov;26(11):1164-74
references.pmid: 15499579
references.citation: Lab Invest. 2010 Apr;90(4):611-9
references.pmid: 20142802
references.citation: Cell. 2009 Apr 17;137(2):356-68
references.pmid: 19379699
references.citation: Lancet. 1991 Feb 9;337(8737):320-2
references.pmid: 1671232
references.citation: Nat Genet. 2004 Sep;36(9):932-4
references.pmid: 15340427
references.citation: Leukemia. 2003 Nov;17(11):2214-9
references.pmid: 14523479
references.citation: Oncogene. 2010 Jan 28;29(4):503-15
references.pmid: 19881539
references.citation: Hematology Am Soc Hematol Educ Program. 2009;:497-506
references.pmid: 20008235
references.citation: Neoplasia. 2007 Jul;9(7):578-88
references.pmid: 17710161
references.citation: Blood. 1993 Nov 15;82(10):2937-42
references.pmid: 8219183
references.citation: Am J Pathol. 2004 Mar;164(3):925-35
references.pmid: 14982846
references.citation: Cancer Cell. 2008 Dec 9;14(6):431-3
references.pmid: 19061834
references.citation: Blood. 2009 Jun 4;113(23):5920-6
references.pmid: 19188663
references.citation: Adv Exp Med Biol. 2005;570:393-421
references.pmid: 18727509
references.citation: Exp Hematol. 2006 Apr;34(4):399-406
references.pmid: 16569586
references.citation: Chromosoma. 1999 Dec;108(7):426-35
references.pmid: 10654081
references.citation: Genetics. 1941 Mar;26(2):234-82
references.pmid: 17247004
references.citation: Nature. 2004 Sep 23;431(7007):461-6
references.pmid: 15329734