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PXD036363-1

PXD036363 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTargeting N-linked Glycosylation for the Therapy of Human Lymphoma
DescriptionDiffuse 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.
HostingRepositoryPRIDE
AnnounceDate2023-04-22
AnnouncementXMLSubmission_2023-04-21_18:28:31.135.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSebastianScheich
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; acetylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos; Q Exactive; Orbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-08-28 03:24:08ID requested
12023-04-21 18:28:31announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: B cell receptor, functional glycoproteomics, NF-kB, phosphoproteomics,Lymphoma, DLBCL
Contact List
Louis M.Staudt
contact affiliationLymphoid Malignancies Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda, Maryland
contact emaillstaudt@mail.nih.gov
lab head
SebastianScheich
contact affiliationLymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
contact emailsebastian.scheich@nih.gov
dataset submitter
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