Published online 11 February 2009
Haematologica, Vol 94, Issue 3, 355-363 doi:10.3324/haematol.13269
Copyright © 2009 by Ferrata Storti Foundation
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Original Article

Comparative analysis of oncogenic properties and nuclear factor-{kappa}B activity of latent membrane protein 1 natural variants from Hodgkin’s lymphoma’s Reed-Sternberg cells and normal B-lymphocytes

Nathalie Faumont1,2,3, Aurélie Chanut3, Alan Benard1,2, Nadine Cogne3, Georges Delsol1,2, Jean Feuillard3, Fabienne Meggetto1,2

1 INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse;
2 Université Toulouse III Paul Sabatier, Institut Claude de Préval, Toulouse and
3 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6101, Centre Hospitalier Universitaire Dupuytren, Université de Limoges, Laboratoire d’Hématologie, Limoges, France

Correspondence: Jean Feuillard, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6101, Centre Hospitalier Universitaire Dupuytren, Université de Limoges, Limoges, France. Email:jean.feuillard{at}unilim.fr

Background: In Epstein-Barr virus-associated Hodgkin’s lymphomas, neoplastic Reed-Sternberg cells and surrounding non-tumor B-cells contain different variants of the LMP1-BNLF1 oncogene. In this study, we raised the question of functional properties of latent membrane protein 1 (LMP1) natural variants from both Reed-Sternberg and non-tumor B-cells.

Design and Methods: Twelve LMP1 natural variants from Reed-Sternberg cells, non-tumor B-cells of Hodgkin’s lymphomas and from B-cells of benign reactive lymph nodes were cloned, sequenced and stably transfected in murine recombinant interleukin-3-dependent Ba/F3 cells to search for relationships between LMP1 cellular origin and oncogenic properties as well as nuclear factor-{kappa}B activation, and apoptosis protection.

Results: LMP1 variants of Reed-Sternberg cell origin were often associated with increased mutation rate and with recurrent genetic events, such as del15bp associated with S to N replacement at codon 309, and four substitutions I85L, F106Y, I122L, and M129I. Oncogenic potential (growth factor-independence plus clonogenicity) was consistently associated with LMP1 variants from Reed-Sternberg cells, but inconstantly for LMP1-variants from non-tumor B-cells. Analysis of LMP1 variants from both normal B-cells and Reed-Sternberg cells indicates that protection against apoptosis through activation of nuclear factor-{kappa}B - whatever the cellular origin of LMP1 - was maintained intact, regardless of the mutational pattern.

Conclusions: Taken together, our results demonstrate that preserved nuclear factor-{kappa}B activity and protection against apoptosis would be the minimal prerequisites for all LMP1 natural variants from both normal and tumor cells in Hodgkin’s lymphomas, and that oncogenic potential would constitute an additional feature for LMP1 natural variants in Reed-Sternberg cells.

Key words: Epstein-Barr virus, LMP1, Hodgkin’s lymphoma, NF-{kappa}B, oncogenic potential.




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