Affinage

CSF3R

Granulocyte colony-stimulating factor receptor · UniProt Q99062

Length
836 aa
Mass
92.2 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CSF3R encodes the granulocyte colony-stimulating factor receptor (G-CSFR), a type I cytokine receptor that transduces G-CSF signals through JAK2-STAT3/STAT5 and MAPK/ERK pathways to drive granulopoiesis, neutrophil mobilization, and hematopoietic progenitor proliferation (PMID:7531515, PMID:18292815, PMID:23656643). Ligand dependence is enforced by membrane-proximal O- and N-glycosylation (at Thr-612/615/618 and Asn-610), which prevents constitutive receptor dimerization; mutations eliminating these glycosylation sites drive ligand-independent JAK-STAT signaling and cellular transformation (PMID:24403076, PMID:30348809, PMID:37116708). Receptor homeostasis is maintained by ubiquitination at Lys-762 (mediated by E3 ligases Fbw7 and E6AP) targeting G-CSFR for proteasomal and lysosomal degradation, and truncation mutations that delete internalization/degradation motifs cause receptor overexpression, enhanced STAT5 activation, and clonal dominance of hematopoietic stem cells (PMID:9885205, PMID:18923646, PMID:18292815). Recessive loss-of-function CSF3R mutations cause severe congenital neutropenia, while somatic gain-of-function mutations—particularly membrane-proximal (e.g., T618I) and cytoplasmic truncation classes that cooperate with co-mutations in CEBPA, RUNX1, or SETBP1—drive chronic neutrophilic leukemia and AML (PMID:24753537, PMID:23656643, PMID:31784538).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1991 High

    Establishing the chromosomal location of CSF3R at 1p35-p34.3 provided the foundational genetic mapping needed for subsequent mutation and linkage studies.

    Evidence In situ hybridization and PCR-based somatic cell hybrid analysis

    PMID:1833306

    Open questions at the time
    • No functional characterization of the locus
    • Regulatory elements not mapped
  2. 1995 High

    Identification of a splice variant lacking the distal C-terminus revealed that the cytoplasmic domain is essential for JAK2 activation and growth signaling, establishing the first domain-function map of G-CSFR.

    Evidence Molecular cloning with BAF3 growth assay and JAK2 kinase activation measurement

    PMID:7531515

    Open questions at the time
    • Specific cytoplasmic residues required for JAK2 coupling not identified
    • Downstream signaling cascade not yet delineated
  3. 1999 High

    Demonstrating that SCN/AML-associated truncation mutations delete a critical internalization domain explained how these mutations cause G-CSF hypersensitivity through defective receptor downmodulation rather than constitutive activation.

    Evidence Functional internalization, ligand binding, and growth signaling assays in transfected cells

    PMID:9885205

    Open questions at the time
    • Molecular identity of the internalization motif not mapped to specific residues
    • Ubiquitin-dependent vs. ubiquitin-independent internalization not distinguished
  4. 2004 High

    G-CSFR knockout mouse pharmacokinetic studies established that receptor-mediated endocytosis is a major pathway for plasma clearance of G-CSF ligand, revealing a receptor-level feedback loop controlling systemic G-CSF availability.

    Evidence G-CSFR knockout mouse with ELISA-based pharmacokinetic analysis of filgrastim and pegfilgrastim

    PMID:15082029

    Open questions at the time
    • Relative contribution of renal vs. receptor-mediated clearance not fully quantified
    • Tissue-specific receptor recycling not addressed
  5. 2008 High

    Three contemporaneous studies established the ubiquitin-proteasome system as central to G-CSFR turnover: K762 was identified as the key ubiquitination site controlling internalization and signaling attenuation, truncation mutant mice revealed STAT5 as the essential downstream effector of clonal dominance, and cell-type-specific routing to proteasomal vs. lysosomal degradation was demonstrated.

    Evidence K762R mutagenesis with temperature-sensitive E1 cell line and proteasome inhibitors; Stat5A/B double-knockout epistasis in mouse HSCs; primary neutrophil proteasome/lysosome inhibitor comparison

    PMID:18292815 PMID:18554923 PMID:18923646

    Open questions at the time
    • E3 ligase(s) responsible for K762 ubiquitination not yet identified at this time
    • Whether STAT5 dependence applies to proximal mutations unknown
    • Structural basis of cell-type-specific routing unexplained
  6. 2009 High

    The T617N transmembrane mutation demonstrated that energetically favorable dimerization of the transmembrane domain is sufficient for constitutive receptor activation, establishing a second mechanism (distinct from glycosylation loss) for ligand-independent signaling and explaining hereditary chronic neutrophilia.

    Evidence Transmembrane domain dimerization assay with xenotransplantation and syngeneic bone marrow engraftment

    PMID:19620628

    Open questions at the time
    • Structural resolution of transmembrane dimer interface lacking
    • Whether downstream pathway usage differs from extracellular-domain activating mutations not tested
  7. 2010 Medium

    Neutrophil elastase was shown to proteolytically cleave the G-CSFR ectodomain, reducing surface expression and inhibiting granulopoiesis, establishing a neutrophil-intrinsic negative feedback loop distinct from internalization-based downregulation.

    Evidence Flow cytometry and western blot of cleavage products with CFU-GM colony assay on primary human bone marrow cells

    PMID:20205821

    Open questions at the time
    • Cleavage site not mapped to a specific residue
    • In vivo relevance not confirmed in genetic models
    • Whether cleavage product retains signaling capacity unknown
  8. 2013 High

    Concurrent studies classified oncogenic CSF3R mutations into membrane-proximal (JAK-pathway-dependent, ruxolitinib-sensitive) and truncation (SRC/TNK2-dependent, dasatinib-sensitive) classes, while the E3 ligase Fbw7 was identified as a GSK3β-dependent mediator of G-CSFR proteasomal degradation controlling STAT3 signaling.

    Evidence In vitro transformation with kinase inhibitor panels and primary patient cells; murine BMT model with ruxolitinib; co-IP and ubiquitination assays with Fbw7/GSK3β

    PMID:23656643 PMID:23820376 PMID:24081659

    Open questions at the time
    • Fbw7-G-CSFR interaction confirmed only in one lab
    • Whether SRC/TNK2 dependence of truncation mutants holds in vivo unclear
    • Clinical validation of dual inhibitor strategy pending
  9. 2014 High

    The T618I mutation was shown to prevent O-glycosylation at Thr-615/618, directly causing ligand-independent dimerization, while compound proximal+truncation mutations showed cooperative transformation — and separately, recessive CSF3R loss-of-function mutations were shown to cause severe congenital neutropenia through disrupted glycosylation and surface trafficking.

    Evidence Glycosylation and dimerization assays in Ba/F3 cells with mutagenesis; patient R308C glycosylation and surface expression analysis; RUNX1-CSF3R co-expression in CD34+ cells

    PMID:24403076 PMID:24523240 PMID:24753537

    Open questions at the time
    • Structural basis of how O-glycan loss permits dimerization unknown
    • Whether R308C neutropenia is fully rescued by downstream pathway activation untested
  10. 2016 High

    In vivo modeling revealed that proximal CSF3R mutations are sufficient for leukemogenesis and require MAPK signaling via the Ksr1 adaptor, with MEK inhibition (trametinib) effective against both proximal and ruxolitinib-resistant compound mutations, identifying an alternative therapeutic vulnerability.

    Evidence Mouse BMT model with whole-genome expression profiling and pharmacological MEK1/2 inhibition

    PMID:28031554

    Open questions at the time
    • Ksr1 mechanism of upregulation by CSF3R mutations not defined
    • Whether MEK inhibition is effective in human CNL not established
  11. 2017 Medium

    Multiple studies expanded the mechanistic repertoire: E6AP was identified as a second E3 ligase targeting G-CSFR for degradation; the W341C extracellular mutation was shown to activate via intermolecular disulfide-bonded dimerization; distal truncation mutations (Q793-Q823) were mapped to loss of a dephosphorylation domain; and truncated G-CSFR was shown to protect against NE-mutant-induced apoptosis via sustained AKT/STAT5/BCL-XL.

    Evidence Co-IP/ubiquitination assays for E6AP; cysteine mutagenesis/dimerization for W341C; degradation/mutagenesis assays for distal truncations; dominant-negative/UPR/apoptosis assays for NE interaction

    PMID:28073911 PMID:28439110 PMID:28578910 PMID:28652245

    Open questions at the time
    • E6AP and Fbw7 substrate specificity overlap not resolved
    • Whether W341C and T618I mutations use identical downstream pathways untested
    • Dephosphorylation domain phosphatase identity unknown
  12. 2018 High

    A comprehensive transformation screen defined four distinct gain-of-function mechanisms (disulfide dimerization, transmembrane polar substitution, enhanced internalization, O-glycosylation loss) and demonstrated that STAT3/ERK activation requires receptor internalization while STAT5 is activated at the cell surface, along with discovery that N-glycosylation at N610 is a critical gatekeeper of ligand dependence.

    Evidence Ba/F3 transformation screen with receptor localization and signaling compartmentalization studies; mass spectrometry N-glycan mapping at N610 with mutagenesis

    PMID:29572350 PMID:30348809

    Open questions at the time
    • Endosomal signaling complex composition uncharacterized
    • How internalized receptor specifically activates STAT3 but not STAT5 mechanistically unexplained
  13. 2019 High

    Cooperating genetic events were mechanistically resolved: CEBPA loss-of-function must precede CSF3R activation for AML through failure to activate differentiation enhancers, and SRSF2 mutations were shown to alter CSF3R mRNA splicing (increasing the V3 isoform) with functional consequences for JAK-STAT signaling.

    Evidence Mouse genetic epistasis with enhancer chromatin profiling for CEBPA; digital PCR splice variant quantitation with SRSF2 KO for splicing

    PMID:31462738 PMID:31784538

    Open questions at the time
    • Whether CEBPA mutation order requirement applies to other CSF3R cooperating mutations unknown
    • Functional consequence of V3 isoform increase in vivo not established
  14. 2022 High

    SRSF2 P95H was shown to directly bind exonic splicing enhancer sequences in CSF3R exon 17, promoting Class IV splicing that expands granulocyte progenitors while impairing differentiation, providing a direct RNA-level mechanism linking spliceosome mutations to aberrant G-CSFR signaling.

    Evidence In vitro splicing assay with CSF3R minigene, ESE deletion mutagenesis, Csf3r-null mouse progenitor add-back

    PMID:35941213

    Open questions at the time
    • Whether other spliceosome mutations (U2AF1, SF3B1) similarly alter CSF3R splicing untested
    • Structural basis of SRSF2 P95H recognition of CSF3R ESE not resolved
  15. 2023 High

    Three advances converged: mass spectrometry confirmed O-glycans (GalNAc, Gal-GalNAc) at T618 as the glycosylation event preventing constitutive activation; ALKBH5-mediated m6A demethylation of CSF3R mRNA was identified as a post-transcriptional activator of emergency granulopoiesis; and CSF3R T618I was shown to cooperate with RUNX1-RUNX1T1 via hedgehog/GLI2 upregulation.

    Evidence Mass spectrometry glycan identification with unbiased mutational screen; RIP-qPCR and ALKBH5 KO mouse model; CD34+ transduction with GLI inhibitor pharmacology

    PMID:37116708 PMID:37841755 PMID:38114747

    Open questions at the time
    • Glycosyltransferase(s) responsible for T618 O-glycosylation not identified
    • Whether ALKBH5-CSF3R axis operates in leukemic cells unknown
    • GLI2 cooperation mechanism not validated in vivo leukemia models

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of how glycosylation prevents receptor dimerization, the identity of glycosyltransferases modifying the membrane-proximal region, the full composition of endosomal signaling complexes that differentially activate STAT3/ERK vs. STAT5, and whether therapeutic targeting of specific CSF3R mutation classes can be translated to clinical outcomes.
  • No high-resolution structure of G-CSFR ectodomain with glycans
  • Glycosyltransferases for membrane-proximal O-glycosylation unidentified
  • Endosomal signaling complex composition unknown
  • Clinical trial data for mutation-class-specific inhibitor strategies lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 7 GO:0005768 endosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2
Partners
ALKBH5FBXW7JAK2SRSF2STAT3STAT5ASTAT5BUBE3A

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Oncogenic CSF3R mutations segregate into two distinct regions (membrane-proximal and truncation) and lead to preferential downstream signaling through SRC family-TNK2 or JAK kinases, respectively, conferring differential sensitivity to kinase inhibitors. Validated by in vitro transformation assays and primary-cell colony drug sensitivity assays. In vitro transformation assay, siRNA kinase screen, small-molecule inhibitor panel, primary-cell colony assay The New England journal of medicine High 23656643
1999 Truncating mutations of G-CSFR found in SCN/AML patients delete a critical internalization domain, resulting in impaired ligand internalization, defective receptor downmodulation, and enhanced growth signaling, explaining the dominant-negative, G-CSF-hypersensitive phenotype. Functional internalization assay, ligand binding assay, growth signaling assay in transfected cells Blood High 9885205
2014 The CSF3R T618I membrane-proximal mutation causes ligand-independent signaling by preventing O-linked glycosylation at residues Thr-615 and Thr-618, which increases receptor dimerization. Truncation mutations instead induce overexpression and ligand hypersensitivity by removing endocytosis/degradation motifs. Combined membrane-proximal + truncation mutations show enhanced cellular transformation compared to either alone. Glycosylation assay, receptor dimerization assay, transformation assay in Ba/F3 cells, mutagenesis The Journal of biological chemistry High 24403076
2013 CSF3R T618I is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model, characterized by granulocyte overproduction and granulocytic infiltration, and this disorder is responsive to JAK1/2 inhibition with ruxolitinib. Murine bone marrow transplantation model, pharmacological JAK inhibition (ruxolitinib) Blood High 24081659
2008 Expression of truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level dependent on exogenous G-CSF. G-CSF-induced proliferation and Stat5 phosphorylation are increased in mutant HSCs, and the proliferative advantage is abrogated in myeloid progenitors lacking both Stat5A and Stat5B, demonstrating that inappropriate Stat5 activation is key to clonal dominance. Mouse genetic model, HSC isolation, phospho-Stat5 assay, Stat5A/B double knockout epistasis The Journal of clinical investigation High 18292815
2009 A T617N missense mutation in the CSF3R transmembrane domain energetically favors dimerization, driving constitutive receptor activation and G-CSF hypersensitivity for proliferation and differentiation, causing hereditary chronic neutrophilia. Demonstrated by transmembrane domain dimerization analysis and xenotransplantation assays. Transmembrane domain dimerization assay, xenotransplantation, syngeneic bone marrow engraftment The Journal of experimental medicine High 19620628
2008 The ubiquitin/proteasome system is required for G-CSFR internalization and degradation. G-CSFR is constitutively ubiquitinated (increasing after ligand binding), and disruption of ubiquitination at lysine 762 (K762R mutant) impairs ligand-induced internalization, enhances Stat5 and Akt activation, and induces hyperproliferative G-CSF responses similar to SCN/AML truncation mutants. Temperature-sensitive E1 ubiquitin enzyme cell line (ts20), K762R mutagenesis, proteasome inhibitor MG132, flow cytometry, signaling assays PloS one High 18923646
2013 The E3 ubiquitin ligase Fbw7 (a component of SCF complex) physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation, reducing STAT3 phosphorylation and inhibiting G-CSF-dependent granulocytic differentiation. GSK3β co-operates with Fbw7 and both are required interdependently for G-CSFR degradation. Co-immunoprecipitation, ubiquitination assay, knockdown, STAT3 phosphorylation assay, granulocytic differentiation assay Biochimica et biophysica acta Medium 23820376
2008 The E3 ubiquitin ligase Fbw7-independent role of the proteasome in G-CSFR regulation: in primary human neutrophils, proteasome inhibition (but not lysosome inhibition) blocks ligand-induced G-CSFR internalization/degradation, contrasting with lysosomal routing in transfected cell lines, demonstrating cell-type-specific post-endocytic routing. ts20 cell line with temperature-sensitive E1 enzyme, chloroquine and MG132 inhibitors, primary neutrophil assay, flow cytometry Cytokine Medium 18554923
2017 E6AP (E3 ubiquitin ligase) physically associates with G-CSFR, targets it for ubiquitin-mediated proteasomal degradation, reduces STAT3 phosphorylation, and inhibits granulocytic differentiation. E6AP knockdown restores G-CSFR signaling and enhances differentiation. The truncation mutant G-CSFR-T718 is also degraded by E6AP but at a slower rate. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, STAT3 phosphorylation assay, differentiation assay Biochimica et biophysica acta. Molecular cell research Medium 28578910
2018 Novel gain-of-function CSF3R mutations transform cells via four distinct mechanisms: (1) cysteine-mediated disulfide bond dimerization (S581C); (2) polar amino acid substitution at transmembrane dimer interface (Thr-640); (3) increased internalization mimicking low G-CSF dose (Glu-524 substitution); (4) hydrophobic substitutions at membrane-proximal O-glycosylation residues (Thr-612, Thr-615, Thr-618). STAT3 and ERK activation require CSF3R internalization, whereas STAT5 activation occurs at the cell surface. Cellular transformation assay in Ba/F3 cells, sequencing, receptor localization studies, signaling assays The Journal of biological chemistry High 29572350
2016 CSF3R proximal mutations (but not truncation mutations alone) are sufficient to induce leukemia in mice. Both proximal and compound (proximal+truncation) mutations require enhanced MAPK signaling through upregulation of the Ksr1 adaptor protein. MEK1/2 inhibition with trametinib suppresses leukemia from both CSF3R proximal and ruxolitinib-resistant compound mutations. Mouse bone marrow transplantation, whole-genome expression profiling, biochemical experiments, pharmacological MEK inhibition Leukemia High 28031554
2017 CSF3R distal cytoplasmic truncation mutations (Q793-Q823) have leukemogenic potential via markedly decreased receptor degradation due to loss of a de-phosphorylation domain (residues N818-F836). Truncations prior to Q823 increase expression of a higher-molecular-weight (glycosylated) receptor band essential for surface expression and oncogenic potential. Sufficient STAT5 activation is required for oncogenic transformation. Transformation assay in Ba/F3 cells, receptor degradation assay, mutagenesis, surface expression analysis, STAT5 signaling assay Leukemia Medium 28439110
1995 A point mutation in the G-CSFR gene creating an altered splice donor site leads to overexpression of an SD isoform that lacks the distal C-terminal region (essential for maturation signaling) but retains the membrane-proximal region. The SD isoform has high affinity for G-CSF but cannot transduce growth signals in BAF3 cells and scarcely activates JAK2 kinase. Molecular cloning, BAF3 growth assay, JAK2 kinase activation assay Blood High 7531515
2017 Disruption of conserved extracellular cysteine pairs in CSF3R leads to either gain- or loss-of-function. The activating W341C mutation in the fibronectin-like type III extracellular domain transforms cells via cysteine-mediated intermolecular disulfide bonds causing receptor dimerization, and primary samples carrying this mutation are sensitive to JAK inhibitors. Transformation assay in Ba/F3 cells, cysteine mutagenesis, dimerization assay, patient sample drug sensitivity Cancer research Medium 28652245
2018 N610 residue of CSF3R is an N-linked glycosylation site (confirmed by mass spectrometry) and primary site of receptor sialylation. Substitution mutations at N610 prevent membrane-proximal N-glycosylation, drive ligand-independent cellular expansion, and activate JAK-STAT signaling, demonstrating that membrane-proximal N-glycosylation maintains ligand dependence of CSF3R. Mass spectrometry glycosylation analysis, Ba/F3 transformation assay, mutagenesis, JAK-STAT signaling assay Cancer research High 30348809
2019 The T618I CSF3R is O-glycosylated but undergoes enhanced spontaneous internalization and degradation. Proteasome inhibition dramatically increases its surface expression. The O-glycosylated T618I receptor is constitutively tyrosine phosphorylated (unlike WT which requires ligand), correlating with constitutive JAK2 activation, and both mutant receptor and JAK2 are constitutively ubiquitinated. Glycosylation assay, internalization assay, proteasome inhibition, tyrosine phosphorylation assay, JAK2 activation assay, ubiquitination assay Biochemical and biophysical research communications Medium 31848046
2010 Neutrophil elastase (NE) proteolytically cleaves G-CSFR at its amino-terminus on human PMN in a time-dependent manner, leading to decreased G-CSFR surface expression and appearance of cleavage fragments, and inhibits G-CSFR-mediated granulopoiesis (CFU-GM formation), establishing a novel negative feedback loop for granulopoiesis regulation. Flow cytometry, western blot of cleavage products, CFU-GM colony assay with primary human bone marrow cells Journal of inflammation (London, England) Medium 20205821
2023 ALKBH5 (m6A RNA demethylase) directly binds CSF3R mRNA (confirmed by RIP-qPCR) and erases m6A methylation on CSF3R mRNA, increasing mRNA stability and CSF3R protein expression, which upregulates cell surface G-CSFR and downstream STAT3 signaling to drive emergency granulopoiesis and neutrophil mobilization. RIP-qPCR, m6A methylation assay, mRNA stability assay, ALKBH5 KO mouse model, STAT3 signaling assay Cellular & molecular immunology High 38114747
2019 Activating CSF3R mutations cooperate with loss-of-function CEBPA mutations to promote AML development at the level of myeloid lineage enhancers, where mutant CEBPA prevents activation of differentiation-associated enhancers. CEBPA mutations must occur as the initial event for leukemia initiation in this cooperative pathway. Mouse genetic models, enhancer chromatin profiling, epistasis testing of mutation order Nature communications High 31784538
2014 Functional studies demonstrated that co-expression of mutated RUNX1 and mutated CSF3R in hematopoietic CD34+ cells leads to elevated G-CSF-induced proliferation with diminished myeloid differentiation. Single-cell analyses confirmed RUNX1 and CSF3R mutations reside in the same malignant clone. CD34+ cell functional assay, single-cell analysis, deep sequencing Blood Medium 24523240
2014 Recessively inherited loss-of-function CSF3R mutations cause severe congenital neutropenia through distinct mechanisms: a homozygous missense mutation (R308C) causes perturbed N-glycosylation and aberrant cell surface localization; compound heterozygous frameshifts cause premature stop codons. Patients have full bone marrow myeloid maturation but do not respond to recombinant G-CSF, establishing functional importance of G-CSFR signaling for peripheral neutrophil numbers. Glycosylation assay, cell surface expression analysis, clinical G-CSF non-response, genetic sequencing Blood Medium 24753537
2004 G-CSF receptor knockout mice demonstrate that G-CSFR-mediated clearance is a major mechanism for plasma clearance of both filgrastim and pegfilgrastim; absence of functional G-CSFR significantly increases AUC, prolongs MRT and half-life, and reduces clearance of both forms of G-CSF. G-CSFR knockout mouse pharmacokinetic study, ELISA-based plasma measurement Pharmacological research High 15082029
2011 Truncated G-CSFR cooperates with the PML-RARα oncogene to accelerate AML development in mice in a G-CSF-dependent fashion, establishing a causal contribution of CSF3R truncation mutations to leukemic transformation when combined with a second oncogenic hit. Mouse bone marrow transplantation with PML-RARα + truncated Csf3r co-expression, G-CSF dependence assay Experimental hematology Medium 21911095
2017 A truncated G-CSFR (d715) found in SCN patients inhibits G-CSF-induced NE expression in a dominant-negative manner and suppresses unfolded protein response and apoptosis induced by SCN-derived NE mutants, associated with sustained AKT and STAT5 activation and augmented BCL-XL expression, providing a mechanism for how CSF3R truncation mutations protect myeloid precursors from NE-mutant-induced apoptosis. Dominant-negative functional assay, UPR assay, apoptosis assay, AKT/STAT5 phosphorylation, BCL-XL expression The Journal of biological chemistry Medium 28073911
2019 SRSF2 mutations alter CSF3R mRNA splicing, increasing the ratio of splice variant V3 (which confers a hypoproliferative phenotype with defective JAK-STAT activation when expressed alone) relative to V1 (wild-type). SRSF2 knockout in KG-1 and normal CD34+ cells decreased the V3/V1 ratio, establishing SRSF2 as a regulator of CSF3R splicing. Digital PCR splice variant quantitation, functional proliferation assay, JAK-STAT activation assay, SRSF2 knockout Leukemia Medium 31462738
2022 SRSF2 P95H mutations promote Class IV CSF3R splicing by binding to exonic splicing enhancer (ESE) sequences in CSF3R exon 17 (confirmed by in vitro splicing assay with CSF3R minigene). Class IV isoform add-back in Csf3r-null mouse progenitors increased granulocyte progenitors with impaired neutrophil differentiation, while Class III produced dysmorphic neutrophils, demonstrating functional consequences of altered CSF3R splicing on granulopoiesis. In vitro splicing assay with CSF3R minigene, ESE deletion mutagenesis, Csf3r-null mouse progenitor add-back, differentiation assay Leukemia High 35941213
2008 LRG-mediated acceleration of G-CSF-driven neutrophil differentiation and CD11b expression correlates with increased phospho-STAT3 but not PU.1 or p27(kip1). This effect requires the transmembrane and cytoplasmic domains of G-CSFR (shown using chimeric EpoR/G-CSFR), identifying a distinct non-redundant G-CSFR signaling pathway for LRG function. Chimeric EpoR/G-CSFR transfection, stable LRG transfection in 32Dcl3 cells, phospho-STAT3 assay, differentiation assay Journal of leukocyte biology Medium 18272588
2023 Activating mutations in CSF3R are enriched at residues normally occupied by N, T, and S (glycosylated amino acids), confirmed by mass spectrometry detection of GalNAc and Gal-GalNAc O-glycans at WT threonine 618. Domain mapping showed the single domain containing residue 618 is sufficient for ligand-independent activity, pointing to glycosylation of hotspot residues as a key regulatory mechanism for CSF3R ligand dependence. Unbiased mutational screen, domain mapping, mass spectrometry glycan identification The Journal of biological chemistry High 37116708
2000 G-CSF infusion in humans dose-independently downregulates its own receptor (CD114) by 75% on neutrophils and induces neutrophil degranulation (CD11b increase >300%), leading to up to 10-fold increase in plasma gelatinase B (MMP-9), which may contribute to neutrophil/stem cell mobilization. Randomized controlled crossover study in healthy volunteers, flow cytometry for CD114 and CD11b, plasma MMP-9 ELISA British journal of haematology Medium 11091218
1991 The CSF3R gene was localized to chromosome 1p35-p34.3 by in situ hybridization and PCR-based somatic cell hybrid analysis. In situ hybridization, PCR with somatic cell hybrids, spot-blot hybridization of sorted chromosomes Genomics High 1833306
2023 CSF3R T618I cooperates with RUNX1-RUNX1T1 fusion to expand hematopoietic progenitors and increase self-renewal in CD34+ cells, with gene expression profiling revealing upregulation of hedgehog signaling/GLI2 as the cooperative mechanism. Both primary hematopoietic cells and SKNO-1 cells expressing CSF3R T618I show increased sensitivity to the GLI inhibitor GANT61. CD34+ cell transduction, gene expression profiling, pharmacological GLI inhibition in primary cells and cell line HemaSphere Medium 37841755

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. The New England journal of medicine 451 23656643
2013 CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia 196 23604229
2006 Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. Blood 174 16985178
2014 An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia 168 24441292
2014 Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 122 24523240
2008 Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. British journal of haematology 101 19120359
2013 The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood 100 24081659
2014 G-CSF and G-CSFR are highly expressed in human gastric and colon cancers and promote carcinoma cell proliferation and migration. British journal of cancer 96 24448357
1995 A point mutation in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene in a case of acute myeloid leukemia results in the overexpression of a novel G-CSF-R isoform. Blood 85 7531515
1999 Deletion of a critical internalization domain in the G-CSFR in acute myelogenous leukemia preceded by severe congenital neutropenia. Blood 79 9885205
2008 Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5. The Journal of clinical investigation 69 18292815
2016 Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors. Blood 68 27034432
2014 Significant clinical response to JAK1/2 inhibition in a patient with CSF3R-T618I-positive atypical chronic myeloid leukemia. Leukemia research reports 68 25180155
2009 An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. The Journal of experimental medicine 63 19620628
2014 Ligand independence of the T618I mutation in the colony-stimulating factor 3 receptor (CSF3R) protein results from loss of O-linked glycosylation and increased receptor dimerization. The Journal of biological chemistry 59 24403076
2014 Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood 59 24753537
1991 Assignment of the human granulocyte colony-stimulating factor receptor gene (CSF3R) to chromosome 1 at region p35-p34.3. Genomics 58 1833306
2018 CSF3R Mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia. Cancer 54 29932212
2004 Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model. Pharmacological research 39 15082029
2017 Clinical significance of CSF3R, SRSF2 and SETBP1 mutations in chronic neutrophilic leukemia and chronic myelomonocytic leukemia. Oncotarget 38 28209919
2014 CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia. Journal of hematology & oncology 37 25316523
2018 Gain-of-function mutations in granulocyte colony-stimulating factor receptor (CSF3R) reveal distinct mechanisms of CSF3R activation. The Journal of biological chemistry 34 29572350
2016 Enhanced MAPK signaling is essential for CSF3R-induced leukemia. Leukemia 34 28031554
2023 The RNA m6A demethylase ALKBH5 drives emergency granulopoiesis and neutrophil mobilization by upregulating G-CSFR expression. Cellular & molecular immunology 33 38114747
2020 G-CSF and G-CSFR Induce a Pro-Tumorigenic Macrophage Phenotype to Promote Colon and Pancreas Tumor Growth. Cancers 31 33036138
2020 Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies. Blood advances 31 33108454
2017 A GCSFR/CSF3R zebrafish mutant models the persistent basal neutrophil deficiency of severe congenital neutropenia. Scientific reports 31 28281657
2019 Immunohistochemical Study on the Expression of G-CSF, G-CSFR, VEGF, VEGFR-1, Foxp3 in First Trimester Trophoblast of Recurrent Pregnancy Loss in Pregnancies Treated with G-CSF and Controls. International journal of molecular sciences 30 31906232
2013 E3 ubiquitin ligase Fbw7 negatively regulates granulocytic differentiation by targeting G-CSFR for degradation. Biochimica et biophysica acta 30 23820376
2020 G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets. Frontiers in immunology 29 33042110
2019 G-CSFR antagonism reduces neutrophilic inflammation during pneumococcal and influenza respiratory infections without compromising clearance. Scientific reports 29 31776393
2019 Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia. Nature communications 29 31784538
2007 The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease. Frontiers in bioscience : a journal and virtual library 29 17127322
2000 Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils. The Journal of infectious diseases 29 10882621
2008 LRG-accelerated differentiation defines unique G-CSFR signaling pathways downstream of PU.1 and C/EBPepsilon that modulate neutrophil activation. Journal of leukocyte biology 28 18272588
2020 Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America 26 32471953
2017 Characterization of the leukemogenic potential of distal cytoplasmic CSF3R truncation and missense mutations. Leukemia 25 28439110
2009 G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia. Haematologica 24 19794089
2021 GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration. American journal of physiology. Gastrointestinal and liver physiology 21 33470903
2011 A truncation mutant of Csf3r cooperates with PML-RARα to induce acute myeloid leukemia in mice. Experimental hematology 21 21911095
2020 SWATH-Proteomics of Ibrutinib's Action in Myeloid Leukemia Initiating Mutated G-CSFR Signaling. Proteomics. Clinical applications 20 32319217
2022 Mutated SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms. Blood 19 35482940
2021 G-CSFR antagonism reduces mucosal injury and airways fibrosis in a virus-dependent model of severe asthma. British journal of pharmacology 19 33609280
2018 A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia. Cancer research 19 30348809
2019 Ultra-Sensitive CSF3R Deep Sequencing in Patients With Severe Congenital Neutropenia. Frontiers in immunology 18 30891028
2016 CD114: A New Member of the Neural Crest-Derived Cancer Stem Cell Marker Family. Journal of cellular biochemistry 18 27428599
2012 Defective G-CSFR signaling pathways in congenital neutropenia. Hematology/oncology clinics of North America 18 23351989
2010 Expression of CD123 and CD114 on the bone marrow cells of patients with myelodysplastic syndrome. Chinese medical journal 18 20819538
2000 Granulocyte colony-stimulating factor (G-CSF) downregulates its receptor (CD114) on neutrophils and induces gelatinase B release in humans. British journal of haematology 18 11091218
2000 Retrovirus-mediated gene transfer of granulocyte colony-stimulating factor receptor (G-CSFR) cDNA into MDS cells and induction of their differentiation by G-CSF. Cytokines, cellular & molecular therapy 18 11108571
2016 Role of CSF3R mutations in the pathomechanism of congenital neutropenia and secondary acute myeloid leukemia. Annals of the New York Academy of Sciences 16 27270496
2015 CSF3R and CALR mutations in paediatric myeloid disorders and the association of CSF3R mutations with translocations, including t(8; 21). British journal of haematology 16 25858548
2008 In vivo expansion of cells expressing acquired CSF3R mutations in patients with severe congenital neutropenia. Blood 16 19020310
2019 Altered expression of CSF3R splice variants impacts signal response and is associated with SRSF2 mutations. Leukemia 14 31462738
2017 Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function. Cancer research 13 28652245
2020 CSF3R truncation mutations in a patient with B-cell acute lymphoblastic leukemia and a favorable response to chemotherapy plus dasatinib. Leukemia research reports 12 32577374
2019 T618I CSF3R mutations in chronic neutrophilic leukemia induce oncogenic signals through aberrant trafficking and constitutive phosphorylation of the O-glycosylated receptor form. Biochemical and biophysical research communications 12 31848046
2010 Neutrophil elastase downmodulates native G-CSFR expression and granulocyte-macrophage colony formation. Journal of inflammation (London, England) 12 20205821
2008 G-CSFR ubiquitination critically regulates myeloid cell survival and proliferation. PloS one 12 18923646
2021 Differential Implications of CSF3R Mutations in t(8;21) and CEBPA Double Mutated Acute Myeloid Leukemia. Clinical lymphoma, myeloma & leukemia 11 34975010
2020 Hypermethylation of CSF3R is a novel cisplatin resistance marker and predictor of response to postoperative chemotherapy in hepatoblastoma. Hepatology research : the official journal of the Japan Society of Hepatology 11 31894653
2017 A Truncated Granulocyte Colony-stimulating Factor Receptor (G-CSFR) Inhibits Apoptosis Induced by Neutrophil Elastase G185R Mutant: IMPLICATION FOR UNDERSTANDING CSF3R GENE MUTATIONS IN SEVERE CONGENITAL NEUTROPENIA. The Journal of biological chemistry 11 28073911
2016 A CSF3R T618I Mutation in a Patient with Chronic Neutrophilic Leukemia and Severe Bleeding Complications. Internal medicine (Tokyo, Japan) 11 26875968
2008 Role of the proteasome in modulating native G-CSFR expression. Cytokine 11 18554923
2020 Promoter hypermethylation in CSF3R induces peripheral neutrophil reduction in benzene-exposure poisoning. Environmental and molecular mutagenesis 10 32329128
2018 Genome sequence and comparative genomic analysis of a clinically important strain CD11-4 of Janibacter melonis isolated from celiac disease patient. Gut pathogens 10 29387173
2025 CSF3R-AS promotes hepatocellular carcinoma progression and sorafenib resistance through the CSF3R/JAK2/STAT3 positive feedback loop. Cell death & disease 8 40155591
2015 CD114 Expression Mediates Melanoma Tumor Cell Growth and Treatment Resistance. Anticancer research 8 26124323
2014 [CSF3R, ASXL1,SETBP1, JAK2 V617F and CALR mutations in chronic neutrophilic leukemia]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 8 25543699
2012 The granulocyte-colony stimulating factor receptor (G-CSFR) interacts with retinoic acid receptors (RARs) in the regulation of myeloid differentiation. Journal of leukocyte biology 8 23136256
2020 Management of a Patient With Congenital Biallelic CSF3R Mutation With GM-CSF. Journal of pediatric hematology/oncology 7 30499904
2024 Analysis of CSF3R mutations in atypical chronic myeloid leukemia and other myeloid malignancies. Annals of diagnostic pathology 6 38642470
2024 CSF3R mutated myeloid neoplasms: Beyond chronic neutrophilic leukemia. Human pathology 6 38879086
2022 Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia. Current oncology (Toronto, Ont.) 6 35200567
2022 Alternatively spliced CSF3R isoforms in SRSF2 P95H mutated myeloid neoplasms. Leukemia 6 35941213
2021 CSF3R T618I, SETBP1 G870S, SRSF2 P95H, and ASXL1 Q780* tetramutation co-contribute to myeloblast transformation in a chronic neutrophilic leukemia. Annals of hematology 6 33822276
2020 Cooperating, congenital neutropenia-associated Csf3r and Runx1 mutations activate pro-inflammatory signaling and inhibit myeloid differentiation of mouse HSPCs. Annals of hematology 6 32821971
2019 Congenital Neutropenia Patient With Hypomorphic Biallelic CSF3R Mutation Responding to GCSF. Journal of pediatric hematology/oncology 6 30028820
2018 Coexisting of bone marrow fibrosis, dysplasia and an X chromosomal abnormality in chronic neutrophilic leukemia with CSF3R mutation: a case report and literature review. BMC cancer 6 29587671
2024 A JAGN1-associated severe congenital neutropenia zebrafish model revealed an altered G-CSFR signaling and UPR activation. Blood advances 5 38739706
2024 Increased blood CSF3R+ myeloid-derived suppressor cell is a predictor for breast cancer recurrence. American journal of cancer research 5 39005677
2020 Application of the Moran Model in Estimating Selection Coefficient of Mutated CSF3R Clones in the Evolution of Severe Congenital Neutropenia to Myeloid Neoplasia. Frontiers in physiology 5 33041834
2020 Effect of the unfolded protein response and oxidative stress on mutagenesis in CSF3R: a model for evolution of severe congenital neutropenia to myelodysplastic syndrome/acute myeloid leukemia. Mutagenesis 5 33511998
2019 Next-generation sequencing reveals unique combination of mutations in cis of CSF3R in atypical chronic myeloid leukemia. Journal of clinical laboratory analysis 5 31692115
2017 Identification of a novel CSF3R-SPTAN1 fusion gene in an atypical chronic myeloid leukemia patient with t(1;9)(p34;q34) by RNA-Seq. Cancer genetics 5 29025591
2014 Prevalence and impact of colony stimulating factor 3 receptor (CSF3R) mutations among Egyptian acute myeloid leukemia patients. Leukemia research 5 24746896
2025 Rnf111 has a pivotal role in regulating development of definitive hematopoietic stem and progenitor cells through the Smad2/3-Gcsfr/NO axis in zebrafish. Haematologica 4 39363867
2020 Eighty-year-old man with rare chronic neutrophilic leukemia caused by CSF3R T618I mutation: A case report and review of literature. World journal of clinical cases 4 33392315
2017 E6AP inhibits G-CSFR turnover and functions by promoting its ubiquitin-dependent proteasome degradation. Biochimica et biophysica acta. Molecular cell research 4 28578910
2013 GCSF-R expression in myelodysplastic and myeloproliferative disorders and blast dysmaturation in CML. American journal of clinical pathology 4 23897249
1999 Association of src-kinase Lyn and non-src-kinase Syk with the granulocyte colony-stimulating factor receptor (G-CSFR) is not abrogated in neutrophils from severe congenital neutropenia patients with point mutations in the G-CSFR mRNA. International journal of hematology 4 10643150
2025 Distribution of different classes of CSF3R mutations and co-mutational pattern in 360 myeloid neoplasia. Annals of hematology 3 39907800
2023 Mutational screens highlight glycosylation as a modulator of colony-stimulating factor 3 receptor (CSF3R) activity. The Journal of biological chemistry 3 37116708
2023 Antineoplastic effects of pharmacological inhibitors of aurora kinases in CSF3RT618I-driven cells. Blood cells, molecules & diseases 3 37839173
2023 CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition. HemaSphere 3 37841755
2023 Germline CSF3R Variant in Chronic Myelomonocytic Leukemia: Linking Genetic Predisposition to Uncommon Hemorrhagic Symptoms. International journal of molecular sciences 3 38003211
2021 Colony-stimulating factor 3 receptor (CSF3R) M696T mutation does not impact on clinical outcomes of a Ph+ acute lymphoblastic leukemia patient. Blood science (Baltimore, Md.) 3 35402839
2018 Expression and role of granulocyte macrophage colony-stimulating factor receptor (GM-CSFR) and granulocyte colony-stimulating factor receptor (G-CSFR) on Ph-positive acute B lymphoblastic leukemia. Hematology (Amsterdam, Netherlands) 3 29338593
2015 Chronic neutrophilic leukemia with overexpression of EVI-1, and concurrent CSF3R and SETBP1 mutations: A case report. Oncology letters 3 26622734
2023 Identification of CD114 Membrane Receptors as a Molecular Target in Medulloblastomas. International journal of molecular sciences 2 36982406