USP7 sustains an active epigenetic program via stabilizing MLL2 and WDR5 in diffuse large B-cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive non-Hodgkin's lymphoma subtype with poor prognosis.
• BCR signaling pathway activation is crucial for ABC-DLBCL survival, but its precise molecular regulation remains incompletely understood.
• Ubiquitin-specific protease 7 (USP7) expression is elevated in DLBCL, particularly in the ABC subtype.

Purpose of the Study:

• To investigate the role of USP7 in the pathogenesis of ABC-DLBCL.
• To explore the therapeutic potential of USP7 inhibition in ABC-DLBCL.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) database for USP7 expression in DLBCL subtypes.
• Inhibition of USP7 enzymatic activity in ABC-DLBCL and GCB-DLBCL cell lines.
• Assessment of BCR signaling components, histone methylation (H3K4me2), and COMPASS complex proteins (WDR5, MLL2) following USP7 inhibition.
• Correlation analysis between USP7 expression and BCR signaling pathway components in patient data.

Main Results:

• USP7 expression is significantly upregulated in ABC-DLBCL compared to GCB-DLBCL.
• USP7 inhibition selectively reduces the viability and downregulates BCR signaling components in ABC-DLBCL cells.
• USP7 inhibition decreases H3K4me2 levels and reduces WDR5 and MLL2 protein expression, indicating disruption of the COMPASS complex.
• USP7 stabilizes WDR5 and MLL2 in ABC-DLBCL cells, contributing to an oncogenic epigenetic program.

Conclusions:

• USP7 plays a critical role in ABC-DLBCL by stabilizing WDR5 and MLL2, thereby organizing an oncogenic epigenetic program.
• Targeting USP7 represents a novel and potentially effective therapeutic strategy for ABC-DLBCL.
• USP7 inhibition may offer advantages over targeting individual BCR signaling components like BTK.