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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 Cancer research
Vol 78
Issue 24
Date 2018 Dec 15
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 Associated with drug Resistance
CSF3R N610H missense gain of function CSF3R N610H lies within the fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). N610H results in increased Stat3 phosphorylation, promotes ligand-independent proliferation, and is transforming in culture (PMID: 30348809).
CSF3R N610Q missense gain of function CSF3R N610Q lies within the fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). N610Q results in increased Stat3 phosphorylation, promotes ligand-independent proliferation, and is transforming in culture (PMID: 30348809).
CSF3R N610S missense gain of function - predicted CSF3R N610S lies within the 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 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
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