HSP110 sustains chronic NF-κB signaling in activated B cell diffuse large B cell lymphoma through MyD88 stabilization.
Fiche publication
Date publication
juin 2018
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen, Pr MARTIN Laurent, Dr JEGO Gaëtan
Tous les auteurs :
Boudesco C, Verhoeyen E, Martin L, Chassagne-Clement C, Salmi L, Mhaidly R, Pangault C, Fest T, Ramla S, Jardin F, Wolz OO, Weber ANR, Garrido C, Jego G
Lien Pubmed
Résumé
Activated B cell diffuse large B cell lymphoma (ABC-DLBCL) is an aggressive lymphoproliferative disorder involving chronic NF-κB activation. Several mutations in the BCR and the MyD88 signaling pathway components, such as MyD88 L265P, are implicated in this aberrant activation. Among heat-shock proteins, HSP110 has recently been identified as a pro- survival and/or proliferation factor in many cancers but its role in ABC-DLBCL survival mechanisms remained to be established. We observed that shRNA-mediated HSP110 silencing decreased the survival of several ABC-DLBCL cell lines, decreased IgM-MyD88 co-localization and subsequent NF-κB signaling. Conversely, over-expression of HSP110 in ABC-DLBCL or non-DLBCL cell lines increased NF-κB signaling, indicating a tight interplay between HSP110 and the NF-κB pathway. Using immunoprecipitation and proximity ligation assays, we identified an interaction between HSP110 and both wild type MyD88 and MyD88 L265P. HSP110 stabilized both MyD88 forms with a stronger effect on MyD88 L265P, therefore facilitating chronic NF-κB activation. Finally, HSP110 expression was higher in lymph-node biopsies of patients with ABC-DLBCL than in normal reactive lymph nodes and a strong correlation was found between the level of HSP110 and MyD88. In conclusion, we identified HSP110 as a regulator of NF-κB signaling through MyD88 stabilization in ABC-DLBCL. This finding reveals HSP110 as a new potential therapeutic target in ABC-DLBCL.
Référence
Blood. 2018 Jun 5;: