Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of biological chemistry	293	19	2018 05 11	7387-7396	J Biol Chem

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
CSF3R	E524A	missense	gain of function - predicted	CSF3R E524A lies within 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 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 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 fibronectin type-III domain 4 of the Csf3r protein (UniProt.org). E524K does not result in increased Stat5 and Erk activity, but confers a gain of function to the Csf3r protein as indicated by increased receptor internalization, Stat3 activation, and transformation in cultured cells (PMID: 29572350).
CSF3R	E524N	missense	gain of function - predicted	CSF3R E524N lies within 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	G644E	missense	unknown	CSF3R G644E lies within the transmembrane domain of the Csf3r protein (UniProt.org). G644E is not transforming in cell culture (PMID: 29572350), but has not been biochemically characterized and therefore, its effect on Csf3r protein function is unknown.
CSF3R	P621A	missense	unknown	CSF3R P621A lies within fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). P621A has been identified in the scientific literature (PMID: 29572350), but has not been biochemically characterized and therefore, its effect on Csf3r protein function is unknown (PubMed, Feb 2024).
CSF3R	S581C	missense	gain of function	CSF3R S581C lies within 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 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.
CSF3R	T612A	missense	gain of function	CSF3R T612A lies within fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). T612A results in cytokine-independent cell growth and increased ligand-dependent phosphorylation of Stat3 and Erk compared to wild-type Csf3r in culture (PMID: 29572350).
CSF3R	T612I	missense	gain of function	CSF3R T612I lies within fibronectin type-III domain 5 of the Csf3r protein (UniProt.org). T612I results in cytokine-independent cell growth and increased ligand-dependent phosphorylation of Stat3 and Erk compared to wild-type Csf3r in culture (PMID: 29572350).
CSF3R	T640I	missense	no effect - predicted	CSF3R T640I lies within the transmembrane domain of the Csf3r protein (UniProt.org). T640I results in cytokine-induced proliferation similar to wild-type protein (PMID: 33108454) and 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	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
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