PXD011118

PXD011118 is an original dataset announced via ProteomeXchange.

Title	A novel germline variant in CSF3R highlights the potent oncogenic effects of loss of N-glycosylation and its implication for therapeutic intervention
Description	Mutations in the colony stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as AML. Herein, we study the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions are potently oncogenic and activate the receptor independently of its ligand, GCSF. These mutations activate the JAK-STAT signaling pathway and confer sensitivity to JAK inhibitors. The N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans, as shown by detailed mass spectrometry analysis. Further analysis demonstrates that N610 is the primary site of sialylation of the receptor. This study demonstrates that membrane-proximal N-linked glycosylation is critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevents membrane proximal N-glycosylation of CSF3R, which then drives ligand-independent neutrophil expansion. Kinase inhibitors block growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation.
HostingRepository	PRIDE
AnnounceDate	2018-11-06
AnnouncementXML	Submission_2018-11-06_08:31:54.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Spiciarich
SpeciesList	scientific name: Arachis hypogaea (Peanut); NCBI TaxID: 3818; scientific name: Arabidopsis thaliana (Mouse-ear cress); NCBI TaxID: 3702; scientific name: Candida albicans (Yeast); NCBI TaxID: 5476; scientific name: Halobacterium salinarum; NCBI TaxID: 2242; scientific name: Brassica napus (Rape); NCBI TaxID: 3708; scientific name: Acyrthosiphon pisum (Pea aphid); NCBI TaxID: 7029; scientific name: Equus caballus (Horse); NCBI TaxID: 9796; scientific name: Enterococcus faecalis (Streptococcus faecalis); NCBI TaxID: 1351; scientific name: Bombyx mori (Silk moth); NCBI TaxID: 7091; scientific name: Caenorhabditis elegans; NCBI TaxID: 6239; scientific name: Hepatitis C virus subtype 1a; NCBI TaxID: 31646; scientific name: Bos taurus (Bovine); NCBI TaxID: 9913; scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Danio rerio (Zebrafish) (Brachydanio rerio); NCBI TaxID: 7955; scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227; scientific name: Helicobacter pylori J99 (Campylobacter pylori J99); NCBI TaxID: 85963; scientific name: Brassica oleracea var. botrytis (Cauliflower); NCBI TaxID: 3715; scientific name: Cicer arietinum (Chickpea) (Garbanzo); NCBI TaxID: 3827; scientific name: Cercopithecus aethiops (Green monkey) (Grivet); NCBI TaxID: 9534; scientific name: Heliocidaris erythrogramma (Sea urchin); NCBI TaxID: 7634; scientific name: Escherichia coli; NCBI TaxID: 562; scientific name: Apis mellifera (Honeybee); NCBI TaxID: 7460; scientific name: Dictyostelium discoideum (Slime mold); NCBI TaxID: 44689; scientific name: Gallus gallus (Chicken); NCBI TaxID: 9031; scientific name: Hordeum vulgare (Barley); NCBI TaxID: 4513; scientific name: Gadus morhua (Atlantic cod); NCBI TaxID: 8049;
ModificationList	TMT6plex-126 reporter fragment; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2018-09-18 01:53:38	ID requested
⏵ 1	2018-11-06 08:31:56	announced

Spiciarich DR, Oh ST, Foley A, Hughes SB, Mauro MJ, Abdel-Wahab O, Press RD, Viner R, Thompson SL, Chen Q, Azadi P, Bertozzi CR, Maxson JE, A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia. Cancer Res, 78(24):6762-6770(2018) [pubmed]

curator keyword: Biomedical

submitter keyword: CSF3R, GCSFR, myeloid leukemia, glycosylation, receptor activation

Prof. Julia Maxson
contact affiliation	Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR.
contact email	maxsonj@ohsu.edu
lab head
David Spiciarich
contact affiliation	• College of Chemistry, University of California Berkeley, Berkeley, CA. • Department of Chemistry Stanford University, Stanford, CA.
contact email	dspiciarich@berkeley.edu
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/2018/11/PXD011118

PRIDE project URI

• PRIDE
  1. PXD011118
     1. Label: PRIDE project
     2. Name: A novel germline variant in CSF3R highlights the potent oncogenic effects of loss of N-glycosylation and its implication for therapeutic intervention