TY  - JOUR
AU  - Scheich, Sebastian
AU  - Chen, Jiji
AU  - Liu, Jiamin
AU  - Schnütgen, Frank
AU  - Enssle, Julius C
AU  - Ceribelli, Michele
AU  - Thomas, Craig J
AU  - Choi, Jaewoo
AU  - Morris, Vivian
AU  - Hsiao, Tony
AU  - Nguyen, Hang
AU  - Wang, Boya
AU  - Bolomsky, Arnold
AU  - Phelan, James D
AU  - Corcoran, Sean
AU  - Urlaub, Henning
AU  - Young, Ryan M
AU  - Häupl, Björn
AU  - Wright, George W
AU  - Huang, Da Wei
AU  - Ji, Yanlong
AU  - Yu, Xin
AU  - Xu, Weihong
AU  - Yang, Yandan
AU  - Zhao, Hong
AU  - Muppidi, Jagan
AU  - Pan, Kuan-Ting
AU  - Oellerich, Thomas
AU  - Staudt, Louis M
TI  - Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas.
JO  - Cancer discovery
VL  - 13
IS  - 8
SN  - 2159-8274
CY  - Philadelphia, Pa.
M1  - DKFZ-2023-01603
SP  - 1862 - 1883
PY  - 2023
AB  - 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.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.
KW  - Humans
KW  - NF-kappa B: metabolism
KW  - Glycosylation
KW  - Signal Transduction
KW  - Lymphoma, Large B-Cell, Diffuse: drug therapy
KW  - Lymphoma, Large B-Cell, Diffuse: genetics
KW  - Lymphoma, Large B-Cell, Diffuse: metabolism
KW  - Phosphatidylinositol 3-Kinases: metabolism
KW  - Cell Line, Tumor
KW  - NF-kappa B (NLM Chemicals)
KW  - Phosphatidylinositol 3-Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37141112
DO  - DOI:10.1158/2159-8290.CD-22-1401
UR  - https://inrepo02.dkfz.de/record/278346
ER  -