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@ARTICLE{Scheich:278346,
author = {S. Scheich and J. Chen and J. Liu and F. Schnütgen$^*$ and
J. C. Enssle and M. Ceribelli and C. J. Thomas and J. Choi
and V. Morris and T. Hsiao and H. Nguyen and B. Wang and A.
Bolomsky and J. D. Phelan and S. Corcoran and H. Urlaub and
R. M. Young and B. Häupl$^*$ and G. W. Wright and D. W.
Huang and Y. Ji and X. Yu and W. Xu and Y. Yang and H. Zhao
and J. Muppidi and K.-T. Pan and T. Oellerich$^*$ and L. M.
Staudt},
title = {{T}argeting {N}-linked {G}lycosylation for the {T}herapy of
{A}ggressive {L}ymphomas.},
journal = {Cancer discovery},
volume = {13},
number = {8},
issn = {2159-8274},
address = {Philadelphia, Pa.},
reportid = {DKFZ-2023-01603},
pages = {1862 - 1883},
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.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.},
keywords = {Humans / NF-kappa B: metabolism / Glycosylation / Signal
Transduction / Lymphoma, Large B-Cell, Diffuse: drug therapy
/ Lymphoma, Large B-Cell, Diffuse: genetics / Lymphoma,
Large B-Cell, Diffuse: metabolism / Phosphatidylinositol
3-Kinases: metabolism / Cell Line, Tumor / NF-kappa B (NLM
Chemicals) / Phosphatidylinositol 3-Kinases (NLM Chemicals)},
cin = {FM01},
ddc = {610},
cid = {I:(DE-He78)FM01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37141112},
doi = {10.1158/2159-8290.CD-22-1401},
url = {https://inrepo02.dkfz.de/record/278346},
}