Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into the activated B-cell (ABC) and germinal center B cell-like (GCB) subtypes. Self-antigen engagement of B-cell receptors (BCR) in ABC tumors induces their clustering, thereby initiating chronic active signal-ing and activation of NF-KB and PI3 kinase. Constitutive BCR signaling is essential in some GCB tumors but primarily activates PI3 kinase. We devised genome-wide CRISPR-Cas9 screens to identify regula-tors of IRF4, a direct transcriptional target of NF-KB and an indicator of proximal BCR signaling in ABC DLBCL. Unexpectedly, inactivation of N-linked protein glycosylation by the oligosaccharyltransferase-B (OST-B) complex reduced IRF4 expression. OST-B inhibition of BCR glycosylation reduced BCR clus-tering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-KB activation. By directly interfering with proximal BCR signaling, OST-B inactivation killed models of ABC and GCB DLBCL, supporting the development of selective OST-B inhibitors for the treatment of these aggressive cancers.

Automated summary

Diffuse large B-cell lymphoma (DLBCL) can be categorized into two subtypes: activated B-cell (ABC) and germinal center B cell-like (GCB). The study found that self-antigen engagement of B-cell receptors (BCR) in ABC tumors triggers clustering, activating chronic active signaling and NF-KB and PI3 kinase. Genome-wide CRISPR-Cas9 screens were used to identify regulators of IRF4, a direct transcriptional target of NF-KB and an indicator of proximal BCR signaling in ABC DLBCL. Inactivation of N-linked protein glycosylation by the OST-B complex reduced IRF4 expression and targeting OST-B inhibition killed models of ABC and GCB DLBCL, suggesting the potential for selective OST-B inhibitors in treating these aggressive cancers.