SIRT1 and HSP90α feed-forward circuit safeguards chromosome segregation integrity in diffuse large B cell lymphomas

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Diffuse Large B-cell Lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with diverse clinical and molecular features.
• A subset, termed 'OxPhos' DLBCL, shows increased oxidative phosphorylation and overexpression of heat shock protein HSP90α.
• The molecular mechanisms driving OxPhos DLBCL pathogenesis remain incompletely understood.

Purpose of the Study:

• To elucidate the pathogenetic circuit involving HSP90α in OxPhos DLBCL.
• To investigate the interaction between HSP90α and SIRT1 in this DLBCL subtype.
• To evaluate the therapeutic potential of targeting the SIRT1-HSP90α axis.

Main Methods:

• Utilized knockdown, chemical inhibition, co-immunoprecipitation, and proximity ligation assays (PLA).
• Assessed chromosome segregation errors via microscopy.
• Evaluated cytotoxicity and drug synergy in DLBCL cell lines.

Main Results:

• Identified a feed-forward circuit where SIRT1 regulates HSP90α expression and HSP90α stabilizes SIRT1 protein.
• Confirmed SIRT1-HSP90α complex formation, significantly higher in OxPhos DLBCL and increased during mitosis.
• Inhibition of SIRT1 and/or HSP90 led to chromosome segregation errors and cytotoxicity in OxPhos DLBCL cells.
• SIRT1 inhibitors demonstrated dose-dependent cytotoxicity and synergized with HSP90 inhibitors.

Conclusions:

• Defined a novel OxPhos-DLBCL-specific pathway involving SIRT1 and HSP90α that impacts mitotic chromosome dynamics.
• This SIRT1-HSP90α interaction represents a potential therapeutic vulnerability in OxPhos DLBCL.
• Targeting this pathway offers a promising strategy for treating this aggressive lymphoma subtype.