Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles

Guffei, Amanda; Sarkar, Rahul; Klewes, Ludger; Righolt, Christiaan H.; Knecht, Hans; Mai, Sabine

doi:10.3324/haematol.2010.030171

Cited by 51 publications

(68 citation statements)

References 41 publications

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“…20 Finally, RS cells contain giant "zebra" chromosomes as a result of multiple breakage-bridge-fusion cycles. 21 These results are consistent with the hypothesis that EBV interacts with the shelterin-telomere complex and that the oncoprotein LMP1 directly or indirectly targets key proteins of it, and by doing so, initiates 3D telomere-related changes in germinal center-derived B cells favoring the formation of H and RS cells.…”

Section: Introductionsupporting

confidence: 80%

“…20 SKY of HL cell lines identifies complex chromosomal rearrangements already in H cells that progress through multiple BBF cycles to end-stage multinuclear RS cells. 21 In these RS cells, g-H2AX, Mre11, and Rad51c are upregulated and TRF2 is mainly cytoplasmic. 8 This is consistent with telomere dysfunction because conditional TRF2 deletion elicits an ataxiatelangectasia-Rad3 (ATM)-mediated telomere damage response with g-H2AX upregulation resulting in telomere fusions and consequently giant chromosomes in mouse fibroblasts 39 as well as in endoreplication and giant hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, it had been shown that an absence or reduction of TRF2 proteins on telomeres results in nonhomologous end joining (NHEJ) of telomeres with formation of giant chromosomes 33 remarkably similar to those observed in RS cells. 21 We therefore hypothesized that LMP1-induced TRF2 suppression could be a major factor in formation of multinucleated cells via an induction of telomere-led genome instability. If that was the case, overriding LMP1-dependent TRF2 suppression by CMV-driven myc-TRF2 expression should block NHEJ and multinucleation induced by LMP1.…”

Section: Constitutive Lmp1 Expression Suppresses Shelterin Proteins Amentioning

confidence: 99%

“…Downregulation of CD99 (mic2) appears to be involved in this process, 49 and the mononuclear precursor H cells exhibit multiple random chromosomal rearrangements. 50,51 These complex chromosomal patterns are the result of ongoing BBF cycles as demonstrated by SKY combined with telomere FISH 21 ; for example, a t(1;17) found in an H cell becomes a four-way translocation in an end-stage RS cell t(1;17;13;18) associated with interstitial telomere signals and telomere-free chromosome ends. 21 This dynamic process of nuclear remodeling probably begins in the few monoclonal circulating B cells 6 or even earlier in activated EBV-infected tonsillar germinal center B cells, which escape immunosurveillance.…”

mentioning

confidence: 99%

“…50,51 These complex chromosomal patterns are the result of ongoing BBF cycles as demonstrated by SKY combined with telomere FISH 21 ; for example, a t(1;17) found in an H cell becomes a four-way translocation in an end-stage RS cell t(1;17;13;18) associated with interstitial telomere signals and telomere-free chromosome ends. 21 This dynamic process of nuclear remodeling probably begins in the few monoclonal circulating B cells 6 or even earlier in activated EBV-infected tonsillar germinal center B cells, which escape immunosurveillance. 35 Substantial LMP1-induced alterations in the expression of several shelterin proteins, which act as gatekeepers for correct DNA replication and normally protect the chromosome ends 52,53 may substantially contribute to the unraveling of the molecular pathogenesis of EBV-associated HL.…”

mentioning

confidence: 99%

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LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates

Lajoie¹,

Lemieux²,

Sawan

et al. 2015

Blood

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Key Points• LMP1 expression in post germinal center B cells results in downregulation of shelterin proteins, telomeric aggregates, and multinuclearity.• LMP1 targets TRF1, TRF2, and POT1 reversibly at the transcriptional/translational level, and TRF2 is essential to block multinuclearity.Hodgkin lymphoma (HL) and Burkitt lymphoma are both germinal center-derived B-cell lymphomas. To assess the consequences of permanent latent membrane protein 1 (LMP1) expression as observed in tumor cells of Epstein-Barr virus (EBV) -associated HL, we analyzed 3-dimensional (3D) telomere dynamics and measured the expression of shelterin proteins at the transcriptional and translational level and their topographic distribution in the EBV-negative Burkitt cell line BJAB stably transfected with an inducible LMP1 system. Stable LMP1 expression led to a highly significant increase of multinucleated cells, nuclear volume, and 3D telomeric aggregates when compared with the LMP1-suppressed BJAB controls. Most importantly, LMP1 induced a significant downregulation of the shelterin components TRF1, TRF2, and POT1 at the transcriptional and translational level, and this downregulation was reversed after resuppression of LMP1.In addition, as revealed by spectral karyotyping, LMP1 induced "outré" giant cells and hypoploid "ghost" cells. This LMP1-induced multinucleation was blocked upon LMP1-independent TRF2 expression. These results show that LMP1-dependent deregulation of telomere stability and nuclear organization via shelterin downregulation, in particular TRF2, favors chromosomal rearrangements. We speculate that telomeric aggregates and ongoing breakage-bridge-fusion cycles lead to disturbed cytokinesis and finally to multinuclearity, as observed in EBV-associated HL. (Blood. 2015;125(13):2101-2110

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Section: Introductionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Constitutive Lmp1 Expression Suppresses Shelterin Proteins Amentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates

Lajoie¹,

Lemieux²,

Sawan

et al. 2015

Blood

View full text Add to dashboard Cite

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Shattered and stitched chromosomes—chromothripsis and chromoanasynthesis—manifestations of a new chromosome crisis?

Righolt

Mai

2012

Genes Chromosomes & Cancer

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Chromothripsis (chromosome shattering) has been described as complex rearrangements affecting single chromosome(s) in one catastrophic event. The chromosomes would be "shattered" and "stitched together" during this event. This phenomenon is proposed to constitute the basis for complex chromosomal rearrangements seen in 2-3% of all cancers and in ∼ 25% of bone cancers. Here we discuss chromothripsis, the use of this term and the evidence presented to support a single catastrophic event that remodels the genome in one step. We discuss why care should be taken in using the term chromothripsis and what evidence is lacking to support its use while describing complex rearrangements.

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Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three‐dimensional nuclear organization of patient‐derived cell lines

Wark

Novak

Sabbaghian

et al. 2013

Genes Chromosomes & Cancer

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PALB2/FANCN is a BRCA1- and BRCA2-interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in PALB2 predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of PALB2 heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient-derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating PALB2 mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q-FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST-1. The PALB2 c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild-type FCLs generated from first-degree relatives (P =1.04E-10 and P =9.68E-15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three PALB2 heterozygous FCLs analyzed when compared with PALB2 wild-type, BRCA1 and BRCA2 heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of PALB2-related cancers.

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Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles

Cited by 51 publications

References 41 publications

LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates

LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates

Shattered and stitched chromosomes—chromothripsis and chromoanasynthesis—manifestations of a new chromosome crisis?

Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three‐dimensional nuclear organization of patient‐derived cell lines

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