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Ref Type Journal Article
PMID (28652245)
Authors Zhang H, Means S, Schultz AR, Watanabe-Smith K, Medeiros BC, Bottomly D, Wilmot B, McWeeney SK, Kükenshöner T, Hantschel O, Tyner JW
Title Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 77 16 2017 08 15 4258-4267 Cancer Res
URL
Abstract Text Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g., T618I), functionally defective mutations in the extracellular domain of the G-CSF receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here, we describe the first activating mutation in the fibronectin-like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain- and loss-of-function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients. Cancer Res; 77(16); 4258-67. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
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 R308C missense loss of function CSF3R R308C lies within fibronectin type-III domain 2 of the Csf3r protein (UniProt.org). R308C confers a loss of function to the Csf3r protein as demonstrated by reduced cell surface expression and impaired downstream signaling (PMID: 24753537), and decreased cell viability (PMID: 28652245) in response to G-CSF stimulation in culture.
CSF3R W341C missense gain of function CSF3R W341C lies within fibronectin type-III domain 3 of the Csf3r protein (UniProt.org). W341C confers a gain of function to the Csf3r protein as demonstrated by increased receptor dimerization, elevated Stat5, Jak2 and Erk activation, and transformation in cultured cells (PMID: 28652245).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CSF3R W341C hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited viability of a cell line expressing CSF3R W341C in culture (PMID: 28652245). 28652245
CSF3R W341C CSF3R W791* hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, (ruxolitinib) inhibited viability of a cell line expressing CSF3R W341C and W791* in culture (PMID: 28652245). 28652245