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Ref Type Journal Article
PMID (29572350)
Authors Zhang H, Coblentz C, Watanabe-Smith K, Means S, Means J, Maxson JE, Tyner JW
Title Gain-of-function mutations in granulocyte colony-stimulating factor receptor (CSF3R) reveal distinct mechanisms of CSF3R activation.
Journal The Journal of biological chemistry
Vol 293
Issue 19
Date 2018 05 11
URL
Abstract Text Granulocyte colony-stimulating factor (G-CSF or CSF3) and its receptor CSF3R regulate granulopoiesis, neutrophil function, and hematopoietic stem cell mobilization. Recent studies have uncovered an oncogenic role of mutations in the CSF3R gene in many hematologic malignancies. To find additional CSF3R mutations that give rise to cell transformation, we performed a cellular transformation assay in which murine interleukin 3 (IL-3)-dependent Ba/F3 cells were transduced with WT CSF3R plasmid and screened for spontaneous growth in the absence of IL-3. Any outgrowth clones were sequenced to identify CSF3R mutations with transformation capacity. We identified several novel mutations and determined that they transform cells via four distinct mechanisms: 1) cysteine- and disulfide bond-mediated dimerization (S581C); 2) polar, noncharged amino acid substitution at the transmembrane helix dimer interface at residue Thr-640; 3) increased internalization by a Glu-524 substitution that mimics a low G-CSF dose; and 4) hydrophobic amino acid substitutions in the membrane-proximal residues Thr-612, Thr-615, and Thr-618. Furthermore, the change in signaling activation was related to an altered CSF3R localization. We also found that CSF3R-induced STAT3 and ERK activations require CSF3R internalization, whereas STAT5 activation occurred at the cell surface. Cumulatively, we have expanded the regions of the CSF3R extracellular and transmembrane domains in which missense mutations exhibit leukemogenic capacity and have further elucidated the mechanistic underpinnings that underlie altered CSF3R expression, dimerization, and signaling activation.

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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 E524A missense gain of function - predicted CSF3R E524A lies within the fibronectin type-III domain 4 of the Csf3r protein (UniProt.org). E524A results in G-CSF-independent cell growth and survival in culture (PMID: 29572350), and therefore, is predicted to lead to a gain of Csf3r protein function.
CSF3R E524D missense no effect - predicted CSF3R E524D lies within the fibronectin type-III domain 4 of the Csf3r protein (UniProt.org). E524D has not been biochemically characterized, but is not transforming in cell culture (PMID: 29572350), and therefore, is predicted to have no effect on Csf3r protein function.
CSF3R E524G missense gain of function - predicted CSF3R E524G lies within the fibronectin type-III domain 4 of the Csf3r protein (UniProt.org). E524G results in G-CSF-independent cell growth and survival in culture (PMID: 29572350), and therefore, is predicted to lead to a gain of Csf3r protein function.
CSF3R E524K missense gain of function CSF3R E524K lies within the fibronectin type-III domain 4 of the Csf3r protein (UniProt.org). E524K does not result in increased Stat5 and Erk activity, but demonstrates increased receptor internalization, Stat3 activation, and transformation in cultured cells (PMID: 29572350), and therefore, leads to a gain of Csf3r protein function.
CSF3R E524N missense gain of function - predicted CSF3R E524N lies within the fibronectin type-III domain 4 of the Csf3r protein (UniProt.org). E524N results in G-CSF-independent cell growth and survival in culture (PMID: 29572350), and therefore, is predicted to lead to a gain of Csf3r protein function.
CSF3R S581C missense gain of function CSF3R S581C lies within the fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). S581C confers a gain of function to the Csf3r protein as demonstrated by increased receptor dimerization and is transforming in cell culture (PMID: 29572350).
CSF3R S581R missense no effect - predicted CSF3R S581R lies within the fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). S581R has not been biochemically characterized, but is not transforming in cell culture (PMID: 29572350), and therefore, is predicted to have no effect on Csf3r protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CSF3R T618I hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited colony formation in transformed bone marrow cells expressing CSF3R T618I in culture (PMID: 29572350). 29572350
CSF3R T618I hematologic cancer sensitive Ruxolitinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Jakafi (ruxolitinib) and Mekinist (trametinib) synergized to inhibit colony formation in transformed bone marrow cells expressing CSF3R T618I in culture, and demonstrated improved efficacy over either agent alone (PMID: 29572350). 29572350
CSF3R T618I hematologic cancer no benefit Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed bone marrow cells expressing CSF3R T618I were not sensitive to Gleevec (imatinib) in culture, demonstrating similar colony formation compared to treatment controls (PMID: 29572350). 29572350
CSF3R T618I hematologic cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited colony formation in transformed bone marrow cells expressing CSF3R T618I in culture (PMID: 29572350). 29572350