Reference Detail

Ref Type

Journal Article

PMID

(30348809)

Authors

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

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	78	24	2018 Dec 15	6762-6770	Cancer Res

URL

Abstract Text

: 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
CSF3R	NCBI	CD114\|GCSFR\|SCN7		CSF3R, colony stimulating factor 3 receptor, encodes a cytokine receptor regulating proliferation and differentiation of myeloid progenitor cells (PMID: 27789332). CSF3R mutations commonly occur in chronic neutrophilic leukemia and acute myeloid leukemia (PMID: 23896413, PMID: 30348809).	Oncogene

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
CSF3R	N610H	missense	gain of function	CSF3R N610H lies within fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). N610H confers a gain of function to the Csf3r protein as demonstrated by increased Stat3 phosphorylation and ligand independent cell growth in culture (PMID: 30348809).
CSF3R	N610Q	missense	gain of function	CSF3R N610Q lies within fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). N610Q confers a gain of function to the Csf3r protein as demonstrated by increased Stat3 phosphorylation and ligand-independent cell growth in culture (PMID: 30348809).
CSF3R	N610S	missense	gain of function - predicted	CSF3R N610S lies within fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). N610S is transforming in cell culture (PMID: 30348809), and therefore, is predicted to lead to a gain of Csf3r protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CSF3R N610S	Advanced Solid Tumor	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Jakafi (ruxolitinib) inhibited growth of transformed cells exxpressing CSF3R N610S in culture (PMID: 30348809).	30348809
CSF3R N610H	Advanced Solid Tumor	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Jakafi (ruxolitinib) inhibited growth of transformed cells expressing CSF3R N610H in culture (PMID: 30348809).	30348809
CSF3R N610H	Advanced Solid Tumor	predicted - sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of transformed cells expressing CSF3R N610H in culture (PMID: 30348809).	30348809
CSF3R N610S	Advanced Solid Tumor	predicted - sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of transformed cells expressing CSF3R N610S in culture (PMID: 30348809).	30348809