A novel germline variant in CSF3R highlights the potent oncogenic effects of loss of N-glycosylation and its implication for therapeutic intervention

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Enterococcus Faecalis (streptococcus Faecalis) Heliocidaris Erythrogramma (sea Urchin) Acyrthosiphon Pisum (pea Aphid) Bombyx Mori (silk Moth) Candida Albicans (yeast) Brassica Oleracea Var. Botrytis (cauliflower) Helicobacter Pylori J99 (campylobacter Pylori J99) Halobacterium Salinarum Drosophila Melanogaster (fruit Fly) Hepatitis C Virus Subtype 1a Escherichia Coli Hordeum Vulgare (barley) Brassica Napus (rape) Arabidopsis Thaliana (mouse-ear Cress) Dictyostelium Discoideum (slime Mold) Gadus Morhua (atlantic Cod) Equus Caballus (horse) Caenorhabditis Elegans Danio Rerio (zebrafish) (brachydanio Rerio) Arachis Hypogaea (peanut) Cercopithecus Aethiops (green Monkey) (grivet) Homo Sapiens (human) Bos Taurus (bovine) Gallus Gallus (chicken) Cicer Arietinum (chickpea) (garbanzo) Apis Mellifera (honeybee)

DISEASE(S): Chronic Neutrophilic Leukemia

SUBMITTER: David Spiciarich  

LAB HEAD: Prof. Julia Maxson

PROVIDER: PXD011118 | Pride | 2018-11-06

REPOSITORIES: Pride