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Cancer Res. 2018 Oct 22. pii: canres.1638.2018. doi: 10.1158/0008-5472.CAN-18-1638. [Epub ahead of print]

A novel germline variant in CSF3R reduces N-glycosylation and exerts potent oncogenic effects in leukemia.

Author information

1
Chemistry, University of California, Berkeley.
2
Division of Hematology, Washington University School of Medicine.
3
Oregon Health & Science University.
4
Clinical Research, Fred Hutchinson Cancer Research Center.
5
Memorial Sloan Kettering Cancer Center.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center.
7
3181 SW Sam Jackson Pk Rd, L113, Oregon Health & Science University.
8
Thermo Fisher Scientific.
9
Fred Hutchinson Cancer Research Center.
10
Complex Carbohydrate Research Center, University of Georgia.
11
Chemistry, Stanford University.
12
Division of Hematology and Medical Oncology, Oregon Health & Science University 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 AML. 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.

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