PXD036363-1

PXD036363 is an original dataset announced via ProteomeXchange.

Title	Targeting N-linked Glycosylation for the Therapy of Human Lymphoma
Description	Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-B and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-B activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-B activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-B and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-B in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.
HostingRepository	PRIDE
AnnounceDate	2023-04-22
AnnouncementXML	Submission_2023-04-21_18:28:31.135.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	SebastianScheich
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-28 03:24:08	ID requested
⏵ 1	2023-04-21 18:28:31	announced

Dataset with its publication pending

submitter keyword: B cell receptor, functional glycoproteomics, NF-kB, phosphoproteomics,Lymphoma, DLBCL

Louis M.Staudt
contact affiliation	Lymphoid Malignancies Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda, Maryland
contact email	lstaudt@mail.nih.gov
lab head
SebastianScheich
contact affiliation	Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
contact email	sebastian.scheich@nih.gov
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/04/PXD036363

PRIDE project URI

• PRIDE
  1. PXD036363
     1. Label: PRIDE project
     2. Name: Targeting N-linked Glycosylation for the Therapy of Human Lymphoma