Cancers, Vol. 10, Pages 414: 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, Vol. 10, Pages 414: 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 doi: 10.3390/cancers10110414

Authors: Radhia M'kacher Monika Frenzel Mustafa Al Jawhari Steffen Junker Corina Cuceu Luc Morat Anne-Laure Bauchet Lev Stimmer Aude Lenain Nathalie Dechamps William M. Hempel Geraldine Pottier Leonhard Heidingsfelder Eric Laplagne Claire Borie Noufissa Oudrhiri Dima Jouni Annelise Bennaceur-Griscelli Bruno Colicchio Alain Dieterlen Theodore Girinsky Raphael Boisgard Jean Bourhis Jacques Bosq Thomas Mehrling Eric Jeandidier Patrice Carde

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.

https://ift.tt/2zhZhly