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Cancer Res. 2018 Dec 15;78(24):6762-6770. doi: 10.1158/0008-5472.CAN-18-1638. Epub 2018 Oct 22.

A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia.

Author information

1
Department of Chemistry, University of California Berkeley, Berkeley, California.
2
Department of Chemistry Stanford University, Stanford, California.
3
Division of Hematology, Washington University School of Medicine, St. Louis, Missouri.
4
Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon.
5
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
6
Memorial Sloan Kettering Cancer Center, New York, New York.
7
Department of Pathology & Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
8
Thermo Fisher Scientific, San Jose, California.
9
Complex Carbohydrate Research Center, The University of Georgia, Athens, Georgia.
10
Howard Hughes Medical Institute, Chevy Chase, Maryland.
11
Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon. maxsonj@ohsu.edu.

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 acute myeloid leukemia. Here, we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK-STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked 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. SIGNIFICANCE: This study reveals the critical importance of membrane-proximal N-linked glycosylation of CSF3R for the maintenance of ligand dependency in leukemia.

PMID:
30348809
PMCID:
PMC6295230
[Available on 2019-12-15]
DOI:
10.1158/0008-5472.CAN-18-1638

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