期刊
BLOOD
卷 132, 期 5, 页码 510-520出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-12-819706
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资金
- fonds europeen de developpement regional (FEDER)
- Ligue Nationale Contre le Cancer
- Conseil Regional de Bourgogne
- French National Research Agency under the Investissements d'Avenir Program [ANR-11-LABX-0021-01-LipSTIC Labex]
- German Research Foundation CRC685 Immunotherapy
- Juniorprofessoren-Programm of the Federal State of Baden-Wurttemberg, Germany
Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoproliferative disorder involving chronic NF-kB 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-kB signaling. Conversely, overexpression of HSP110 in ABC-DLBCL or non-DLBCL cell lines increased NF-kB signaling, indicating a tight interplay between HSP110 and the NF-kB 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-kB 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-kB signaling through MyD88 stabilization in ABC-DLBCL. This finding reveals HSP110 as a new potential therapeutic target in ABC-DLBCL.
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