BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive subtype with poor prognosis.
• Chronic activation of the CARD11-BCL10-MALT1 (CBM) signaling complex is a hallmark of ABC-DLBCL.
• Recurrent somatic mutations in BCL10 affect CBM complex polymerization and signaling.

Purpose of the Study:

• To investigate the functional consequences of distinct BCL10 mutations in ABC-DLBCL.
• To determine the differential impact of BCL10 mutations on response to targeted therapies.
• To establish BCL10 mutations as biomarkers for precision medicine in ABC-DLBCL.

Main Methods:

• Structure-function analysis of BCL10 mutants.
• Biochemical assays to assess BCL10 polymerization and CBM complex activity.
• In vitro studies evaluating drug sensitivity to BTK and MALT1 inhibitors.

Main Results:

• BCL10 mutations were classified into two distinct functional groups: CARD domain missense mutations and C-terminal truncations.
• CARD missense mutations enhanced BCL10 filament formation and stabilized the CBM complex.
• Truncating mutations disrupted MALT1-mediated inhibition of BCL10 polymerization.
• Both BCL10 mutation classes conferred resistance to BTK inhibitors.
• Truncating BCL10 mutations, but not CARD missense mutations, led to hypersensitivity to MALT1 inhibitors.

Conclusions:

• BCL10 mutations are key drivers of CBM complex dysregulation in ABC-DLBCL.
• Specific BCL10 mutation types dictate differential responses to BTK and MALT1 inhibitors.
• BCL10 mutations serve as predictive biomarkers for guiding targeted therapy selection in ABC-DLBCL.