A multiprotein supercomplex controlling oncogenic signalling in lymphoma.

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• B cell receptor (BCR) signaling is a therapeutic target in B cell lymphomas, but its inhibition benefits only a subset of diffuse large B cell lymphoma (DLBCL) patients.
• Activated B cell-like (ABC) DLBCL subtypes show poor outcomes and rely on BCR signaling for NF-κB activation.
• Mutations in CD79A, CD79B, and MYD88 are common in ABC DLBCL, with MYD88(L265P) being prevalent.

Purpose of the Study:

• To determine the molecular basis for exceptional clinical responses to the BTK inhibitor ibrutinib in DLBCL.
• To elucidate the cooperation between CD79B and MYD88 mutations in promoting BCR signaling dependence.
• To identify novel therapeutic strategies for molecularly defined DLBCL subsets.

Main Methods:

• Genome-wide CRISPR-Cas9 screening
• Functional proteomics
• Analysis of cell lines and patient biopsies
• Co-localization studies with mTOR on endolysosomes

Main Results:

• Discovery of a multiprotein supercomplex (My-T-BCR) involving MYD88, TLR9, and BCR in ibrutinib-responsive DLBCL.
• The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, driving pro-survival NF-κB and mTOR signaling.
• Combined inhibition of BCR and mTOR signaling synergistically reduced My-T-BCR supercomplex formation and function.
• My-T-BCR supercomplexes characterized ibrutinib-responsive DLBCL and distinguished responders from non-responders.

Conclusions:

• The My-T-BCR supercomplex represents a novel mode of oncogenic BCR signaling in DLBCL.
• This supercomplex provides mechanistic insight into synergistic toxicity of combined BCR and mTOR inhibitors.
• My-T-BCR supercomplexes serve as biomarkers for ibrutinib response and guide rational drug design for specific DLBCL subsets.