title: 3D nuclear organization of telomeres in the Hodgkin cell lines U-HO1 and U-HO1-PTPN1: PTPN1 expression prevents the formation of very short telomeres including "t-stumps".
abstract: BACKGROUND
  In cancer cells the three-dimensional (3D) telomere organization of interphase nuclei into a telomeric disk is heavily distorted and aggregates are found. In Hodgkin's lymphoma quantitative FISH (3D Q-FISH) reveals a major impact of nuclear telomere dynamics during the transition form mononuclear Hodgkin (H) to diagnostic multinuclear Reed-Sternberg (RS) cells. In vitro and in vivo formation of RS-cells is associated with the increase of very short telomeres including "t-stumps", telomere loss, telomeric aggregate formation and the generation of "ghost nuclei".
  
  
  RESULTS
  Here we analyze the 3D telomere dynamics by Q-FISH in the novel Hodgkin cell line U-HO1 and its non-receptor protein-tyrosine phosphatase N1 (PTPN1) stable transfectant U-HO1-PTPN1, derived from a primary refractory Hodgkin's lymphoma. Both cell lines show equally high telomerase activity but U-HO1-PTPN differs from U-HO1 by a three times longer doubling time, low STAT5A expression, accumulation of RS-cells (p < 0.0001) and a fourfold increased number of apoptotic cells.As expected, multinuclear U-HO1-RS-cells and multinuclear U-HO1-PTPN1-RS-cells differ from their mononuclear H-precursors by their nuclear volume (p < 0.0001), the number of telomeres (p < 0.0001) and the increase in telomere aggregates (p < 0.003). Surprisingly, U-HO1-RS cells differ from U-HO1-PTPN1-RS-cells by a highly significant increase of very short telomeres including "t-stumps" (p < 0.0001).
  
  
  CONCLUSIONS
  Abundant RS-cells without additional very short telomeres including "t-stumps", high rate of apoptosis, but low STAT5A expression, are hallmarks of the U-HO1-PTPN1 cell line. These characteristics are independent of telomerase activity. Thus, PTPN1 induced dephosphorylation of STAT5 with consecutive lack of Akt/PKB activation and cellular arrest in G₂, promoting induction of apoptosis, appears as a possible pathogenetic mechanism deserving further experimental investigation.
authors.affiliation: CHUS, Université de Sherbrooke, Québec, Canada. hans.knecht@USherbrooke.ca
authors.forename: Hans
authors.initials: H
authors.lastname: Knecht
authors.forename: Silke
authors.initials: S
authors.lastname: Brüderlein
authors.forename: Silke
authors.initials: S
authors.lastname: Wegener
authors.forename: Daniel
authors.initials: D
authors.lastname: Lichtensztejn
authors.forename: Zelda
authors.initials: Z
authors.lastname: Lichtensztejn
authors.forename: Bruno
authors.initials: B
authors.lastname: Lemieux
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D016195:G2 Phase; D006689:Hodgkin Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D017404:In Situ Hybridization, Fluorescence; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism / Q000648:ultrastructure*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1