Advertisement

HSP110 sustains chronic NF-κB signaling in activated B cell diffuse large B cell lymphoma through MyD88 stabilization

Christophe Boudesco, Els Verhoeyen, Laurent Martin, Catherine Chassagne-Clement, Leila Salmi, Rana Mhaidly, Céline Pangault, Thierry Fest, Selim Ramla, Fabrice Jardin, Olaf-Oliver Wolz, Alexander N.R. Weber, Carmen Garrido and Gaetan Jego

Key points

  • HSP110 sustains chronic NF-κB signaling in activated B cell diffuse large B cell lymphoma through MyD88 stability.

  • HSP110 is highly expressed in cells of patients with activated B cell diffuse large B cell lymphoma and correlates with MyD88 expression.

Abstract

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.

  • Submitted December 1, 2017.
  • Accepted May 30, 2018.