Independent mechanisms lead to genomic instability in Hodgkin lymphoma: Microsatellite or chromosomal instability

Corina Cuceu, Bruno Colicchio, Eric Jeandidier, Steffen Junker, François Plassa, Grace Shim, Justyna Mika, Monika Frenzel, Mustafa A.L. Jawhari, William M. Hempel, Grainne O’Brien, Aude Lenain, Luc Morat, Theodore Girinsky, Alain Dieterlen, Joanna Polanska, Christophe Badie, Patrice Carde, Radhia M’Kacher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed highMSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. TheMC-HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL andMC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS andMC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL.

Original languageEnglish
Article number233
JournalCancers
Volume10
Issue number7
DOIs
Publication statusPublished - 13 Jul 2018

Bibliographical note

Funding Information:
This work was supported by a grant from the European Community’s Seventh Framework Program (EURATOM) contracts Fission-2011-249689 (DoReMi), SUT grant BKM/508/RAU1/2017t.27(JM) and Cell Environment grant from Metasystems. We are indebted to: Hugues de Thé (Laboratoire de biochimie B, Hopital Saint-Louis, Paris) for TP53 and MSI investigations, Sylvie chevillard (Laboratoire de Cancérologie Expérimentale (LCE), CEA, iRCM, Université Paris-Saclay) for transcriptome analysis, Lewandowski Daniel for flow cytometry investigations (Inserm U967, CEA/DRF/IBFJ/iRCM/LRTS), Nancy Zaarour and Pascal Bertrand (INSERM UMR 967 iRCM/CEA) for lamin B1 staining, Francis Finot and André Essahli (Genevolution laboratory Porcheville, France) for micronucleus investigations, Andreas Plesch and Leonhard Heidingsfelder (Metasystems company) for cytogenetic analysis. We also thank Annelise Bennaceur-Griscelli (UMRS935 Service d’hématologie moléculaire et cytogénétique Paul brousse CHU) for her help to achieve this work. Special thank for Annie Vernique, Micheline Arnoux, Catherine Ferrapie, Wendy Kerbrat, and Wala Najar for technical help.

Funding Information:
Funding: This work was supported by a grant from the European Community’s Seventh Framework Program (EURATOM) contracts Fission-2011-249689 (DoReMi), SUT grantBKM/508/RAU1/2017t.27(JM) and Cell Environment grant from Metasystems.

Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Chromosomal instability
  • Dicentric
  • Hodgkin lymphoma
  • MSI
  • P53
  • Telomere dysfunction

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