Establishment and Characterization of a Reliable Xenograft Model of Hodgkin Lymphoma Suitable for the Study of Tumor Origin and the Design of New Therapies

Cancers

Noufissa Oudrhiri¹  Claire Borie¹  Annelise Bennaceur-Griscelli¹  Dima Jouni¹  Jacques Bosq²  Eric Jeandidier³  Patrice Carde⁴  Theodore Girinsky⁵  Jean Bourhis⁵  Bruno Colicchio⁶  Alain Dieterlen⁶  Steffen Junker⁷  Raphael Boisgard⁸  Geraldine Pottier⁸  Leonhard Heidingsfelder⁹  Thomas Mehrling^1,10  Nathalie Dechamps^1,11  Anne-Laure Bauchet^1,12  Lev Stimmer^1,12  Eric Laplagne^1,13  Monika Frenzel^1,14  WilliamM. Hempel^1,14  Aude Lenain^1,14  Corina Cuceu^1,14  Radhia M’kacher^1,14  Mustafa Al Jawhari^1,14  Luc Morat^1,14 

[1] APHP-Hopital Paul Brousse Université Paris Sud/ESteam Paris Inserm UMR 935, 94800 Villejuif, France;Departement of Anapathology, Gustave Roussy Cancer Campus, University Paris-Saclay, 94805 Vilejuif, France;Department of Genetic, Groupe Hospitalier de la Région de Mulhouse Sud-Alsace, 68093 Mulhouse, France;Department of Medicine, Gustave Roussy Cancer Campus, University Paris-Saclay, 94805 Villejuif, France;Department of Radiation Oncology, Gustave Roussy Cancer Campus, University Paris-Saclay, 94805 Villejuif, France;IRIMAS, Institut de Recherche en Informatique, Mathématiques, Automatique et Signal, Université de Haute-Alsace, 68093 Mulhouse, France;Institute of Biomedicine, University of Aarhus, DK-8000 Aarhus C, Denmark;Laboratoire d’Imagerie Moléculaire Expérimentale Groupe d’Imagerie du Petit Animal CEA/DSV/I2BM/SHFJ/U1023, University Paris-Saclay, 91400 Orsay, France;MetaSystems GmbH, Robert-Bosch-Str. 6D, 68804 Altlussheim, Germany;Mundipharma-EDO GmbH, CH-4020 Basel, Switzerland;Platform for Cell Sorting, CEA, iRCM, 92265 Fontenay aux Roses, France;Platform for Experimental Pathology PathEX/CRC MIRCen/CEA-INSERM, University Paris-Saclay, 92265 Fontenay aux Rroses, France;Pole Concept, 75016 Paris, France;Radiobiology and Oncology Laboratory, CEA, iRCM, University Paris-Saclay, 92 265 Fontenay aux Roses, France;

关键词: Hodgkin lymphoma;    animal model;    CD30−/CD15−;    telomere dysfunction;    telomerase;    EDO-S101;   

DOI  :  10.3390/cancers10110414

来源: DOAJ

【 摘 要 】

To identify the cells responsible for the initiation and maintenance of Hodgkin lymphoma (HL) cells, we have characterized a subpopulation of HL cells grown in vitro and in vivo with the aim of establishing a reliable and robust animal model for HL. To validate our model, we challenged the tumor cells in vivo by injecting the alkylating histone-deacetylase inhibitor, EDO-S101, a salvage regimen for HL patients, into xenografted mice. Methodology: Blood lymphocytes from 50 HL patients and seven HL cell lines were used. Immunohistochemistry, flow cytometry, and cytogenetics analyses were performed. The in vitro and in vivo effects of EDO-S101 were assessed. Results: We have successfully determined conditions for in vitro amplification and characterization of the HL L428-c subline, containing a higher proportion of CD30−/CD15− cells than the parental L428 cell line. This subline displayed excellent clonogenic potential and reliable reproducibility upon xenografting into immunodeficient NOD-SCID-gamma (−/−)(NSG) mice. Using cell sorting, we demonstrate that CD30−/CD15− subpopulations can gain the phenotype of the L428-c cell line in vitro. Moreover, the human cells recovered from the seventh week after injection of L428-c cells into NSG mice were small cells characterized by a high frequency of CD30−/CD15− cells. Cytogenetic analysis demonstrated that they were diploid and showed high telomere instability and telomerase activity. Accordingly, chromosomal instability emerged, as shown by the formation of dicentric chromosomes, ring chromosomes, and breakage/fusion/bridge cycles. Similarly, high telomerase activity and telomere instability were detected in circulating lymphocytes from HL patients. The beneficial effect of the histone-deacetylase inhibitor EDO-S101 as an anti-tumor drug validated our animal model. Conclusion: Our HL animal model requires only 10³ cells and is characterized by a high survival/toxicity ratio and high reproducibility. Moreover, the cells that engraft in mice are characterized by a high frequency of small CD30−/CD15− cells exhibiting high telomerase activity and telomere dysfunction.

【 授权许可】

Unknown