Journal Article

DKFZ-2023-01603

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas.

Scheich, S. ; Chen, J. ; Liu, J. ; Schnütgen, F.DKFZ* ; Enssle, J. C. ; Ceribelli, M. ; Thomas, C. J. ; Choi, J. ; Morris, V. ; Hsiao, T. ; Nguyen, H. ; Wang, B. ; Bolomsky, A. ; Phelan, J. D. ; Corcoran, S. ; Urlaub, H. ; Young, R. M. ; Häupl, B.DKFZ* ; Wright, G. W. ; Huang, D. W. ; Ji, Y. ; Yu, X. ; Xu, W. ; Yang, Y. ; Zhao, H. ; Muppidi, J. ; Pan, K.-T. ; Oellerich, T.DKFZ* ; Staudt, L. M.

2023
Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/2159-8290.CD-22-1401

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.

Keyword(s): Humans (MeSH) ; NF-kappa B: metabolism (MeSH) ; Glycosylation (MeSH) ; Signal Transduction (MeSH) ; Lymphoma, Large B-Cell, Diffuse: drug therapy (MeSH) ; Lymphoma, Large B-Cell, Diffuse: genetics (MeSH) ; Lymphoma, Large B-Cell, Diffuse: metabolism (MeSH) ; Phosphatidylinositol 3-Kinases: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; NF-kappa B ; Phosphatidylinositol 3-Kinases

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 25 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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