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Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas.
- Source :
-
Cancer discovery [Cancer Discov] 2023 Aug 04; Vol. 13 (8), pp. 1862-1883. - Publication Year :
- 2023
-
Abstract
- 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 signaling and activation of NF-κB 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 regulators of IRF4, a direct transcriptional target of NF-κB 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 clustering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-κB 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.<br />Significance: DLBCL depends on constitutive BCR activation and signaling. There are currently no therapeutics that target the BCR directly and attenuate its pathologic signaling. Here, we unraveled a therapeutically exploitable, OST-B-dependent glycosylation pathway that drives BCR organization and proximal BCR signaling. This article is highlighted in the In This Issue feature, p. 1749.<br /> (©2023 American Association for Cancer Research.)
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 13
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 37141112
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-22-1401