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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 ABC-DLBCL through MyD88 stability.

  • HSP110 is highly expressed in cells of patients with ABC-DLBCL and correlates with MyD88 expression.

Publisher's Note: There is a Blood Commentary on this article in this issue.

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 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 prosurvival and/or proliferation factor in many cancers, but its role in ABC-DLBCL survival mechanisms remained to be established. We observed that short hairpin RNA–mediated HSP110 silencing decreased the survival of several ABC-DLBCL cell lines and decreased immunoglobulin M-MyD88 co-localization and subsequent NF-κB signaling. Conversely, overexpression 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. By 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, thus facilitating chronic NF-κB activation. Finally, HSP110 expression was higher in lymph node biopsies from 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.
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