{"gene":"CSF3R","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2013,"finding":"CSF3R mutations segregate into two distinct classes—membrane-proximal (e.g., T618I) and cytoplasmic truncation mutations—that signal through distinct downstream kinases: membrane-proximal mutations preferentially activate JAK kinases, while truncation mutations preferentially signal through SRC family-TNK2 kinases, conferring differential sensitivity to kinase inhibitors.","method":"In vitro transformation assays, small-molecule kinase inhibitor panels, siRNA screens on primary leukemia cells","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA screen, inhibitor panels, transformation assays) replicated across patient samples; foundational mechanistic paper","pmids":["23656643"],"is_preprint":false},{"year":2014,"finding":"The T618I (membrane-proximal) CSF3R mutation causes ligand-independent receptor activation by preventing O-linked glycosylation at Thr-615/Thr-618 residues, which increases receptor dimerization. In contrast, truncation mutations induce receptor overexpression and ligand hypersensitivity by removing endocytosis/degradation motifs. Combining both mutation types on the same allele leads to enhanced cellular transformation compared to either alone.","method":"Mutagenesis of O-glycosylation sites, receptor dimerization assays, cell transformation assays (Ba/F3), receptor expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, dimerization assays, and transformation assays in a single rigorous study","pmids":["24403076"],"is_preprint":false},{"year":1999,"finding":"A critical internalization domain in the G-CSFR cytoplasmic region is deleted in truncation mutants found in SCN/AML patients; deletion of this domain results in impaired ligand internalization, defective receptor downmodulation, and enhanced growth signaling, explaining the dominant-negative hypersensitivity phenotype.","method":"Ligand internalization assays, receptor downmodulation studies, growth signaling assays in transfected cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct functional assays with defined receptor mutants demonstrating mechanistic basis of dominant-negative phenotype","pmids":["9885205"],"is_preprint":false},{"year":2008,"finding":"Expression of truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level dependent on exogenous G-CSF, mediated through increased G-CSF-induced proliferation and enhanced Stat5 phosphorylation. The proliferative advantage is abrogated in myeloid progenitors lacking both Stat5A and Stat5B, and is reduced in mice expressing a truncated Csf3r engineered to have impaired Stat5 activation.","method":"Murine bone marrow transplantation, Stat5 knockout epistasis, phosphorylation assays, Stat5 target gene transcription analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis with Stat5 knockout plus multiple in vivo models, replicated across multiple approaches in one study","pmids":["18292815"],"is_preprint":false},{"year":2013,"finding":"The CSF3R T618I mutation is sufficient to drive a lethal myeloproliferative disorder (overproduction of granulocytes, spleen/liver infiltration) in a murine bone marrow transplantation model, and disease is sensitive to pharmacologic JAK1/2 inhibition with ruxolitinib (reduced WBC, reduced spleen weight).","method":"Murine bone marrow transplantation model, ruxolitinib treatment, hematologic and histologic analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo reconstitution model with defined mutation plus pharmacological validation","pmids":["24081659"],"is_preprint":false},{"year":2009,"finding":"A T617N CSF3R transmembrane domain mutation energetically favors receptor dimerization, leading to constitutive receptor activation and hypersensitivity to G-CSF for proliferation and differentiation, causing hereditary chronic neutrophilia.","method":"Structural/energetic analysis of transmembrane dimerization, xenotransplantation and syngeneic mouse bone marrow engraftment assays, family clinical study","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo engraftment models plus transmembrane dimerization analysis, single lab","pmids":["19620628"],"is_preprint":false},{"year":2008,"finding":"The G-CSFR is constitutively ubiquitinated, with ubiquitination increasing after ligand binding. Abrogation of ubiquitin attachment at K762 (the residue deleted in SCN/AML truncation mutants) impairs ligand-induced internalization, prolongs Stat5 and Akt activation after G-CSF withdrawal, and enhances proliferation and survival.","method":"Site-directed mutagenesis (K762R), ubiquitination assays, internalization assays, signaling (Stat5, Akt phosphorylation), proliferation/survival assays in transfected cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with multiple orthogonal functional assays (ubiquitination, internalization, signaling, proliferation) in one study","pmids":["18923646"],"is_preprint":false},{"year":2008,"finding":"The ubiquitin/proteasome system is required for G-CSFR internalization and degradation: in cells with a temperature-sensitive E1 ubiquitin-activating enzyme, ligand-induced receptor internalization is inhibited. In primary human neutrophils, proteasome inhibition (but not lysosome inhibition) blocks internalization/degradation of the activated G-CSFR.","method":"Temperature-sensitive E1 ubiquitin-activating enzyme cell lines, chloroquine/MG132 pharmacological inhibition, flow cytometry/western blot in primary neutrophils","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal approaches (genetic E1 loss-of-function, pharmacological inhibition) in both cell lines and primary cells","pmids":["18554923"],"is_preprint":false},{"year":2013,"finding":"Fbw7 (an SCF E3 ubiquitin ligase substrate-recognition subunit) physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation; Fbw7-mediated G-CSFR downregulation reduces STAT3 phosphorylation. Fbw7 and GSK3β are interdependent in targeting G-CSFR for degradation—neither alone can degrade G-CSFR when the other is knocked down.","method":"Co-immunoprecipitation, ubiquitination assays, knockdown experiments, STAT3 phosphorylation assays, granulocytic differentiation assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown, single lab with multiple orthogonal approaches","pmids":["23820376"],"is_preprint":false},{"year":2017,"finding":"E6AP (an E3 ubiquitin ligase) physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation, reducing STAT3 phosphorylation and inhibiting granulocytic differentiation. E6AP knockdown restores G-CSFR expression and signaling.","method":"Co-immunoprecipitation, ubiquitination assays, knockdown experiments, STAT3 phosphorylation and differentiation assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional knockdown, single lab","pmids":["28578910"],"is_preprint":false},{"year":2010,"finding":"Neutrophil elastase (NE) proteolytically cleaves G-CSFR at its amino-terminus on human PMN in a time-dependent manner, releasing cleavage fragments into conditioned media and reducing receptor surface expression. NE treatment of bone marrow progenitors also inhibits granulocyte-macrophage colony formation (CFU-GM).","method":"Flow cytometry, western blot, conditioned media analysis for cleavage fragments, CFU-GM colony assay","journal":"Journal of inflammation (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of proteolytic cleavage plus functional colony assay, single lab","pmids":["20205821"],"is_preprint":false},{"year":2014,"finding":"A homozygous Arg308Cys CSF3R missense mutation causes perturbed N-glycosylation and aberrant (reduced) surface localization of the receptor, resulting in SCN with full myeloid bone marrow maturation but no response to recombinant G-CSF.","method":"Genetic analysis of two SCN families, functional analysis of surface expression and N-glycosylation, clinical G-CSF response testing","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mutation with defined molecular consequence (glycosylation/surface expression defect) plus clinical phenotype, two unrelated families","pmids":["24753537"],"is_preprint":false},{"year":1995,"finding":"A point mutation at the SD splice donor site in the G-CSFR gene in a case of AML leads to overexpression of a novel isoform (SD) lacking the distal C-terminal cytoplasmic maturation-signaling region; the SD isoform has high G-CSF affinity but is scarcely capable of activating JAK2 and fails to transduce growth signals in BAF3 cells.","method":"Splice site mutation identification, G-CSF binding assay (affinity), JAK2 activation assay, BAF3 growth signaling assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of isoform with JAK2 activation and growth signaling assays, single study","pmids":["7531515"],"is_preprint":false},{"year":2019,"finding":"CSF3R T618I mutations cause constitutive tyrosine phosphorylation of the O-glycosylated receptor form and constitutive ubiquitination of both the mutant receptor and JAK2; the T618I receptor undergoes enhanced spontaneous internalization and degradation (proteasome-dependent), resulting in markedly decreased surface expression.","method":"Proteasome inhibitor treatment, immunoprecipitation, phosphotyrosine blotting, surface expression analysis in transfected cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical approaches (phosphorylation, ubiquitination, internalization assays), single lab","pmids":["31848046"],"is_preprint":false},{"year":2018,"finding":"Using a cellular transformation screen in Ba/F3 cells, four distinct mechanisms of CSF3R gain-of-function mutations were identified: (1) cysteine/disulfide bond-mediated dimerization (S581C); (2) polar substitution at transmembrane helix dimer interface (T640); (3) increased internalization mimicking low G-CSF dose (E524 substitutions); (4) hydrophobic substitutions in membrane-proximal residues (T612, T615, T618). Additionally, CSF3R-induced STAT3 and ERK activations require receptor internalization, whereas STAT5 activation occurs at the cell surface.","method":"Ba/F3 cellular transformation screen, sequencing of outgrowth clones, receptor localization studies, signaling assays (STAT3, STAT5, ERK) with internalization inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — unbiased functional screen with mechanistic follow-up including localization studies and pathway-specific signaling dissection, multiple orthogonal methods","pmids":["29572350"],"is_preprint":false},{"year":2017,"finding":"CSF3R distal cytoplasmic truncation mutations (Q793–Q823) have leukemogenic potential due to markedly decreased receptor degradation, attributed to loss of a de-phosphorylation domain (residues N818–F836). All truncations prior to Q823 increase expression of the higher-molecular-weight (higher-glycosylated) CSF3R band, which is essential for surface expression and oncogenic potential. Sufficient STAT5 activation is required for oncogenic potential.","method":"Ba/F3 transformation assays, receptor degradation assays, STAT5 activation assays, western blot for receptor glycoforms","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transformation assays plus mechanistic receptor degradation studies, single lab","pmids":["28439110"],"is_preprint":false},{"year":2016,"finding":"CSF3R proximal mutations alone are leukemogenic (90-day latency in mice) while truncation mutations alone cannot induce leukemia; compound mutations (proximal + truncation on same allele) are leukemogenic with shorter latency (23 days). Upregulation of MAPK adaptor Ksr1 and enhanced MAPK signaling are critical for leukemogenesis by CSF3R proximal and compound mutants; MEK1/2 inhibition by trametinib suppresses leukemia from both mutation types including ruxolitinib-resistant compound mutations.","method":"Murine retroviral bone marrow transplantation models, whole-genome expression profiling, biochemical MAPK assays, trametinib pharmacological inhibition","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse models with epistatic analysis, expression profiling, and pharmacological validation, multiple orthogonal approaches","pmids":["28031554"],"is_preprint":false},{"year":2017,"finding":"A W341C extracellular domain CSF3R mutation transforms cells via cysteine-mediated intermolecular disulfide bonds leading to receptor dimerization. Disruption of original cysteine pairs in the CSF3R extracellular domain results in either gain- or loss-of-function depending on the specific pair disrupted.","method":"Ba/F3 transformation assays, disulfide bond/dimerization analysis, JAK inhibitor sensitivity testing","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transformation assay with biochemical dimerization analysis, single lab","pmids":["28652245"],"is_preprint":false},{"year":2018,"finding":"The N610 residue of CSF3R is part of a consensus N-linked glycosylation motif and is the primary site of sialylation; mass spectrometry confirmed complex N-glycans at this site. N610 mutations prevent membrane-proximal N-glycosylation and drive ligand-independent cellular expansion, demonstrating that membrane-proximal N-linked glycosylation is critical for maintaining ligand dependence of the receptor.","method":"Mass spectrometry glycan mapping, mutagenesis of N610, proliferation/transformation assays, JAK inhibitor sensitivity testing","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry glycan confirmation plus mutagenesis plus functional transformation assay, single rigorous study with orthogonal methods","pmids":["30348809"],"is_preprint":false},{"year":2023,"finding":"Unbiased mutational screening confirmed that activating CSF3R mutations are enriched at glycosylated residues (asparagine, threonine, serine); mass spectrometry confirmed glycosylation at multiple CSF3R residues including GalNAc and Gal-GalNAc O-glycans at WT Thr618. The single CSF3R domain containing residue 618 is sufficient for ligand-independent activity.","method":"Protein domain mapping, unbiased mutational screen in Ba/F3 cells, mass spectrometry glycan identification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry glycan mapping plus domain mapping plus mutational screen, multiple orthogonal methods in single study","pmids":["37116708"],"is_preprint":false},{"year":2000,"finding":"G-CSF dose-independently downregulates its own receptor (CD114) on neutrophil surfaces by ~75% in humans and induces neutrophil degranulation (CD11b upregulation) and gelatinase B release (~10-fold increase in plasma); endotoxin (LPS) also downmodulates G-CSFR on neutrophils in vivo in humans.","method":"Randomized controlled human endotoxemia study and G-CSF infusion study with flow cytometry for receptor expression, plasma gelatinase B measurement","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo human experiments with flow cytometry receptor quantification and functional readouts","pmids":["11091218","10882621"],"is_preprint":false},{"year":2004,"finding":"G-CSF receptor-mediated clearance is an important mechanism for plasma clearance of both filgrastim and pegfilgrastim: G-CSFR knockout mice show significantly greater AUC, longer half-life, longer MRT, and lower clearance compared to wild-type mice for both drugs at both doses tested.","method":"G-CSFR knockout mice vs. wild-type pharmacokinetic comparison with ELISA-based plasma drug measurement","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout model with defined pharmacokinetic readout, single study","pmids":["15082029"],"is_preprint":false},{"year":2008,"finding":"LRG (leucine-rich alpha2-glycoprotein) expression is induced by G-CSF in myeloid cells; stable LRG expression accelerates G-CSF-mediated neutrophil differentiation and CD11b induction correlating with increased phospho-STAT3, but this acceleration is not seen in cells expressing a chimeric EpoR/G-CSFR (EpoR extracellular + G-CSFR transmembrane/cytoplasmic domains) stimulated with Epo, suggesting LRG acts through G-CSFR-specific extracellular/ligand-binding signals.","method":"Stable LRG transfection in 32Dcl3 cells, chimeric EpoR/G-CSFR signaling experiments, STAT3 phosphorylation, CD11b flow cytometry","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric receptor epistasis plus stable transfection with pathway readout, single lab","pmids":["18272588"],"is_preprint":false},{"year":2017,"finding":"A truncated G-CSFR mutant (d715, from SCN patient) inhibits G-CSF-induced NE expression in a dominant-negative manner and suppresses unfolded protein response and apoptosis induced by the SCN-derived NE G185R mutant, associated with sustained AKT and STAT5 activation and augmented BCL-XL expression.","method":"Dominant-negative expression of G-CSFR d715, NE expression assays, UPR/apoptosis assays, AKT/STAT5 phosphorylation, BCL-XL western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling readouts with defined mutant receptor, single lab","pmids":["28073911"],"is_preprint":false},{"year":2019,"finding":"Three CSF3R mRNA splice variants exist in hematopoietic cells (V1=wild-type, V3, V4). V3 expression alone confers a hypoproliferative phenotype with defective JAK-STAT activation; coexpression of V1 with V3 rescues proliferative responses. SRSF2 mutations increase the V3/V1 ratio; SRSF2 knockout decreases the V3/V1 ratio.","method":"Digital PCR splice variant quantitation, functional proliferation assays, JAK-STAT activation assays, SRSF2 knockout in KG-1 and CD34+ cells","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of splice variant with pathway readout plus genetic SRSF2 manipulation, single lab","pmids":["31462738"],"is_preprint":false},{"year":2022,"finding":"SRSF2 P95H mutation promotes increased expression of CSF3R Class IV splice isoform by binding to exonic splicing enhancer (ESE) sequences in CSF3R exon 17; deletion of either ESE motif decreases Class IV transcripts. Class IV isoform add-back in Csf3r-null mouse progenitors increases granulocyte progenitors with impaired neutrophil differentiation. Class III isoform produces dysmorphic neutrophils.","method":"In vitro splicing assays with CSF3R minigene, ESE deletion mutagenesis, Csf3r-null mouse progenitor reconstitution, CD34+ cell G-CSF differentiation assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro splicing assay with mutagenesis plus in vivo reconstitution in null cells, multiple orthogonal methods","pmids":["35941213"],"is_preprint":false},{"year":2014,"finding":"Cooperating CSF3R and RUNX1 mutations co-occur in the same malignant clone in CN/AML patients. Hematopoietic CD34+ cells coexpressing mutated RUNX1 and mutated CSF3R show elevated G-CSF-induced proliferation with diminished myeloid differentiation.","method":"Single-cell analysis confirming co-occurrence in same clone, functional G-CSF proliferation and differentiation assays of CD34+ cells coexpressing both mutants","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-cell clonal analysis plus functional CD34+ cell assays, single lab","pmids":["24523240"],"is_preprint":false},{"year":2011,"finding":"Truncated G-CSFR cooperates with PML-RARα to induce AML in mice in a G-CSF-dependent fashion, significantly shortening AML latency, demonstrating a causal role for CSF3R truncation mutations in leukemic transformation.","method":"Murine retroviral co-expression bone marrow transplantation model, G-CSF dependency testing, hematologic/histologic AML characterization","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo murine leukemia cooperation model with G-CSF dependency, single lab","pmids":["21911095"],"is_preprint":false},{"year":2023,"finding":"ALKBH5 (m6A RNA demethylase) directly binds CSF3R mRNA and erases m6A methylation on it, increasing CSF3R mRNA stability and protein expression, thereby upregulating cell surface G-CSFR expression and downstream STAT3 signaling in neutrophils during bacterial infection.","method":"RIP-qPCR (direct ALKBH5-CSF3R mRNA binding), ALKBH5 knockout mice, mRNA stability assays, surface G-CSFR flow cytometry, STAT3 phosphorylation assays","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP-qPCR confirmed direct binding, knockout model, multiple functional readouts including mRNA stability, surface expression, and signaling","pmids":["38114747"],"is_preprint":false},{"year":2020,"finding":"G-CSF/G-CSFR signaling promotes an IL-10-producing, FoxP3-expressing inhibitory Treg phenotype in both CD4+ and CD8+ T cells; G-CSFR-/- T cells exhibit increased IFNγ and IL-17A production and greater cytotoxic activity against tumors. Adoptive transfer of G-CSFR-/- macrophages into tumor-bearing mice also shows higher NOS2/NO production and greater tumor cytotoxicity vs. WT macrophages.","method":"G-CSFR knockout mice, adoptive transfer of WT vs G-CSFR-/- T cells and macrophages, cytokine multiplex, flow cytometry, in vitro/in vivo cytotoxicity assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer experiments with defined cellular phenotyping and functional readouts, single lab","pmids":["33042110"],"is_preprint":false},{"year":2021,"finding":"GCSF binds to GCSFR and activates the SOCS3-JAK-STAT3 signaling pathway in hepatocytes, and GCSF deficiency alleviates HFD-induced insulin resistance and hepatic steatosis in mice.","method":"GCSF knockout mice on HFD, primary hepatocyte treatment, SOCS3/JAK/STAT3 pathway analysis, liver immune cell flow cytometry","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus in vitro hepatocyte mechanistic pathway analysis, single lab","pmids":["33470903"],"is_preprint":false},{"year":2024,"finding":"Enhanced MAPK signaling in CSF3R-driven leukemia upregulates DUSP1 expression to suppress apoptosis; genetic deletion of Dusp1 confers synthetic lethality to CSF3R-induced leukemia in mice. DUSP1 depletion activates JNK1/2, inducing BIM and P53 expression and suppressing BCL2 to trigger selective apoptosis in leukemic cells. Combined BCI (DUSP1 inhibitor) + MEK inhibitor cures CSF3R-induced leukemia in preclinical mice.","method":"Genetic Dusp1 deletion in murine CSF3R leukemia model, BIM/P53/BCL2 signaling analysis, pharmacological combination treatment in vivo","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout demonstrating synthetic lethality plus mechanistic signaling analysis, single lab","pmids":["38531054"],"is_preprint":false},{"year":1999,"finding":"Src-family kinase Lyn and non-Src kinase Syk associate with the G-CSFR in neutrophils from SCN patients expressing truncated G-CSFR; Syk association is retained because the Syk binding motif (aa 727–747) is upstream of the truncation sites, confirming normal G-CSFR is also expressed in these patients.","method":"Co-immunoprecipitation of Lyn and Syk with G-CSFR in neutrophils","journal":"International journal of hematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP experiment in patient neutrophils, no functional follow-up","pmids":["10643150"],"is_preprint":false},{"year":2019,"finding":"The T618I CSF3R mutation retains O-glycosylation but the O-glycosylated T618I receptor form is constitutively tyrosine phosphorylated and constitutively ubiquitinated along with JAK2; proteasome inhibition markedly increases T618I surface expression, indicating enhanced proteasome-dependent receptor turnover as a mechanism of decreased T618I surface expression.","method":"Proteasome inhibitor assays, immunoprecipitation/phosphotyrosine blotting, ubiquitination assays in transfected cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays establishing constitutive phosphorylation and ubiquitination mechanism, single lab","pmids":["31848046"],"is_preprint":false},{"year":2019,"finding":"SETBP1 mutations promote self-renewal of CSF3R-mutated hematopoietic progenitors in vitro, prevent terminal differentiation, and accelerate leukemia progression in vivo through upregulation of Myc and Myc target gene expression programs (reversible by LSD1 inhibitors).","method":"In vitro progenitor colony replating assays, in vivo mouse leukemia models, transcriptomic and epigenomic profiling, LSD1 inhibitor treatment","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo models with transcriptomic/epigenomic mechanistic characterization, single lab","pmids":["35482940"],"is_preprint":false},{"year":2019,"finding":"Activating CSF3R mutations cooperate with CEBPA loss-of-function mutations at the level of myeloid lineage enhancers: mutant CEBPA prevents activation of a subset of differentiation-associated enhancers, and CEBPA mutations must occur as the initial event before CSF3R mutations for AML initiation.","method":"Murine AML models with defined mutation order, chromatin profiling (enhancer activation analysis), epistasis experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo epistasis with enhancer profiling, mechanistic at chromatin level, single lab","pmids":["31784538"],"is_preprint":false},{"year":2025,"finding":"Dual Asxl1Y588X and Csf3rT621I mutations cause expansion of myeloid-biased long-term HSCs and enhanced neutrophil differentiation with activation of inflammatory pathways. Asxl1 truncation enhances CSF3RT618I-driven neutrophil differentiation and increases H3K4me1 at neutrophil-associated enhancers. The expected decrease in H2AK119ub in Asxl1-mutant cells is reversed when CSF3R is also mutated.","method":"Double-mutant mouse model, HSC flow cytometric analysis, ChIP-seq (H3K4me1, H2AK119ub), transcriptomic profiling, myeloid differentiation assays","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-mutant mouse model with epigenomic characterization, single lab","pmids":["39777477"],"is_preprint":false}],"current_model":"CSF3R encodes the G-CSF receptor, a cytokine receptor whose ligand-dependent signaling is regulated by O- and N-linked glycosylation (which maintain ligand dependence by preventing constitutive dimerization), ubiquitin/proteasome-mediated internalization and degradation (with E3 ligases Fbw7, E6AP, and GSK3β targeting K762), and post-activation downregulation via NE-mediated ectodomain cleavage or receptor internalization; oncogenic mutations cluster into two mechanistically distinct classes—membrane-proximal mutations (e.g., T618I) that abolish O-glycosylation and promote constitutive receptor dimerization and ligand-independent JAK/STAT and MAPK signaling, and cytoplasmic truncation mutations that delete internalization and ubiquitination motifs to cause receptor overexpression and G-CSF hypersensitivity with preferential SRC-family signaling—while cooperating mutations in RUNX1, CEBPA, SETBP1, or ASXL1 further promote leukemic transformation through distinct chromatin and transcriptional mechanisms."},"narrative":{"mechanistic_narrative":"CSF3R encodes the granulocyte colony-stimulating factor receptor (G-CSFR/CD114), a cytokine receptor that couples G-CSF binding to JAK/STAT5, STAT3, and MAPK signaling to drive granulocytic proliferation and differentiation [PMID:18292815, PMID:29572350, PMID:28031554]. Ligand dependence is enforced by membrane-proximal glycosylation: O-linked glycosylation at Thr-615/Thr-618 and N-linked glycosylation at Asn-610 prevent spontaneous dimerization, and unbiased mutational screens confirm that activating mutations are enriched at these glycosylated serine, threonine, and asparagine residues [PMID:24403076, PMID:30348809, PMID:37116708]. Receptor output is constrained by ubiquitin/proteasome-dependent internalization and degradation, which requires the ubiquitin-activating enzyme E1 and is targeted by the E3 ligases Fbw7 (interdependently with GSK3β) and E6AP, with ubiquitination at Lys-762 limiting STAT5/STAT3/Akt signaling; loss of these C-terminal motifs underlies receptor overexpression in disease [PMID:18923646, PMID:18554923, PMID:23820376, PMID:28578910]. Oncogenic mutations fall into two mechanistically distinct classes: membrane-proximal mutations such as T618I that abolish glycosylation, promote constitutive dimerization and ligand-independent JAK/STAT signaling, and are leukemogenic alone via enhanced MAPK signaling; and cytoplasmic truncation mutations that delete internalization/ubiquitination motifs to cause G-CSF hypersensitivity and preferential SRC-family-TNK2 signaling, transforming only in cooperation with other lesions [PMID:23656643, PMID:24403076, PMID:9885205, PMID:28031554]. Membrane-proximal mutations confer ruxolitinib sensitivity in vivo, while MAPK dependence renders both classes sensitive to MEK inhibition, and DUSP1 is a synthetic-lethal vulnerability of CSF3R-driven leukemia [PMID:24081659, PMID:28031554, PMID:38531054]. Truncation- and proximal-mutant disease is further driven by cooperating lesions in RUNX1, CEBPA, SETBP1, ASXL1, and by SRSF2-directed missplicing of CSF3R that generates differentiation-impairing isoforms [PMID:28031554, PMID:35941213, PMID:24523240, PMID:35482940, PMID:31784538, PMID:39777477]. Inherited CSF3R missense and transmembrane mutations cause both hereditary chronic neutrophilia (gain-of-function dimerization) and severe congenital neutropenia (loss of surface expression) [PMID:19620628, PMID:24753537].","teleology":[{"year":1995,"claim":"Established that the distal cytoplasmic C-terminus is required for G-CSFR to transduce growth signals, defining the maturation-signaling region whose loss appears in disease isoforms.","evidence":"AML-derived SD splice isoform lacking the distal C-terminus assayed for G-CSF binding, JAK2 activation, and BAF3 growth signaling","pmids":["7531515"],"confidence":"Medium","gaps":["Single isoform from one case","Did not define which residues mediate JAK2 coupling"]},{"year":1999,"claim":"Identified a cytoplasmic internalization domain deleted in SCN/AML truncation mutants as the mechanistic basis of defective receptor downmodulation and hypersensitive growth signaling.","evidence":"Ligand internalization, receptor downmodulation, and growth assays with defined truncation mutants in transfected cells","pmids":["9885205"],"confidence":"High","gaps":["Did not identify the E3 ligases or ubiquitination sites involved","Mechanism of dominant-negative behavior over WT receptor not fully resolved"]},{"year":2008,"claim":"Defined ubiquitin/proteasome-dependent control of receptor turnover, showing constitutive and ligand-enhanced ubiquitination at K762 limits the duration of STAT5/Akt signaling.","evidence":"K762R mutagenesis, ubiquitination/internalization/signaling assays, temperature-sensitive E1 cells, and proteasome inhibition in primary neutrophils","pmids":["18923646","18554923"],"confidence":"High","gaps":["E3 ligases not yet identified in these studies","Relationship between K762 ubiquitination and lysosomal vs proteasomal routing partly unresolved"]},{"year":2008,"claim":"Demonstrated in vivo that truncated G-CSFR confers a G-CSF-dependent HSC clonal advantage operating through STAT5, linking receptor truncation to a defined downstream effector.","evidence":"Murine bone marrow transplantation with Stat5A/B knockout epistasis and STAT5-impaired truncated receptor","pmids":["18292815"],"confidence":"High","gaps":["Does not address transformation to overt leukemia by truncation alone","STAT5 target genes driving proliferation not exhaustively mapped"]},{"year":2009,"claim":"Showed a transmembrane CSF3R mutation can energetically favor dimerization and cause hereditary chronic neutrophilia, establishing constitutive dimerization as a disease mechanism.","evidence":"Transmembrane dimerization energetics, mouse engraftment, and family clinical study of T617N","pmids":["19620628"],"confidence":"Medium","gaps":["Single lab/family","Whether T617N predisposes to leukemic transformation not established"]},{"year":2010,"claim":"Identified neutrophil elastase as a post-activation negative regulator that cleaves the G-CSFR ectodomain to reduce surface expression and constrain granulocyte colony formation.","evidence":"NE treatment of human PMN with flow cytometry, cleavage-fragment western blot, and CFU-GM assays","pmids":["20205821"],"confidence":"Medium","gaps":["Cleavage site not precisely mapped","Physiological contribution relative to ubiquitin-mediated turnover unclear"]},{"year":2013,"claim":"Defined the two-class model of CSF3R oncogenic mutations with distinct kinase dependencies and showed T618I alone drives a JAK-inhibitor-sensitive myeloproliferative disorder.","evidence":"Inhibitor panels, siRNA screens, transformation assays on patient cells, and a ruxolitinib-treated T618I mouse model","pmids":["23656643","24081659"],"confidence":"High","gaps":["Molecular trigger of membrane-proximal activation not yet defined here","Truncation-class transformation requirements for cooperating lesions not addressed"]},{"year":2013,"claim":"Identified Fbw7 as an E3 ligase that, interdependently with GSK3β, ubiquitinates G-CSFR to dampen STAT3 signaling and granulocytic differentiation.","evidence":"Co-immunoprecipitation, ubiquitination, knockdown, and STAT3/differentiation assays","pmids":["23820376"],"confidence":"Medium","gaps":["Single lab","Degron sequence recognized by Fbw7 on G-CSFR not mapped"]},{"year":2014,"claim":"Pinpointed loss of O-glycosylation at Thr-615/Thr-618 as the molecular cause of T618I-driven ligand-independent dimerization, and showed compound proximal+truncation alleles enhance transformation.","evidence":"O-glycosylation site mutagenesis, dimerization, and Ba/F3 transformation assays","pmids":["24403076"],"confidence":"High","gaps":["Did not resolve N-linked contribution","Structural basis of glycosylation-controlled dimerization not determined"]},{"year":2014,"claim":"Established a loss-of-function CSF3R disease axis: an Arg308Cys mutation perturbs N-glycosylation and reduces surface localization, causing SCN unresponsive to G-CSF.","evidence":"Genetic analysis of two SCN families with surface expression, N-glycosylation, and clinical G-CSF response testing","pmids":["24753537"],"confidence":"Medium","gaps":["Two families only","Trafficking step impaired by the mutation not defined"]},{"year":2014,"claim":"Showed CSF3R and RUNX1 mutations co-occur in the same clone and cooperatively enhance proliferation while blocking differentiation, framing CSF3R as a cooperating lesion in CN/AML.","evidence":"Single-cell clonal analysis and functional CD34+ co-expression proliferation/differentiation assays","pmids":["24523240"],"confidence":"Medium","gaps":["Mechanism of RUNX1/CSF3R synergy at transcriptional level not defined","Single lab"]},{"year":2017,"claim":"Expanded the negative-regulator landscape by identifying E6AP as a second E3 ligase degrading G-CSFR and dampening STAT3-driven differentiation.","evidence":"Co-immunoprecipitation, ubiquitination, knockdown, and STAT3/differentiation assays","pmids":["28578910"],"confidence":"Medium","gaps":["Single lab","Hierarchy/overlap with Fbw7-mediated degradation unresolved"]},{"year":2017,"claim":"Resolved the leukemogenic mechanism of distal truncations as loss of a de-phosphorylation domain causing reduced degradation, and tied oncogenicity to the higher-glycosylated surface receptor form and sufficient STAT5 activation.","evidence":"Ba/F3 transformation, receptor degradation, glycoform western blots, and STAT5 assays","pmids":["28439110"],"confidence":"Medium","gaps":["Identity of the phosphatase recruited to the deleted domain not established","Single lab"]},{"year":2017,"claim":"Demonstrated that extracellular cysteine substitutions (W341C) transform via disulfide-mediated dimerization, broadening the mechanisms of ligand-independent activation.","evidence":"Ba/F3 transformation, disulfide/dimerization analysis, and JAK inhibitor sensitivity testing","pmids":["28652245"],"confidence":"Medium","gaps":["Frequency of extracellular-domain mutations in patients not assessed","Single lab"]},{"year":2017,"claim":"Showed a truncated G-CSFR can act dominant-negatively to suppress NE-induced UPR and apoptosis via sustained AKT/STAT5 and BCL-XL, linking receptor truncation to survival of SCN-derived clones.","evidence":"Dominant-negative d715 expression with UPR/apoptosis and AKT/STAT5/BCL-XL readouts","pmids":["28073911"],"confidence":"Medium","gaps":["Single lab","Direct contribution to leukemic progression in vivo not tested here"]},{"year":2018,"claim":"Provided an unbiased mechanistic taxonomy of CSF3R gain-of-function mutations and showed that STAT3/ERK activation requires receptor internalization whereas STAT5 acts at the surface, spatially partitioning downstream signaling.","evidence":"Ba/F3 transformation screen, outgrowth sequencing, localization, and pathway-specific signaling with internalization inhibitors","pmids":["29572350"],"confidence":"High","gaps":["Endosomal scaffolds mediating STAT3/ERK activation not identified","In vivo relevance of compartmentalized signaling not tested"]},{"year":2018,"claim":"Identified Asn-610 as the primary N-linked sialylation site whose loss drives ligand-independent expansion, establishing membrane-proximal N-glycosylation as a second glycan-based guardrail of ligand dependence.","evidence":"Mass spectrometry glycan mapping, N610 mutagenesis, transformation, and JAK inhibitor sensitivity","pmids":["30348809"],"confidence":"High","gaps":["Interplay between N610 and O-glycosylation in dimerization control not dissected","Single lab"]},{"year":2016,"claim":"Defined MAPK signaling, via Ksr1 upregulation, as a critical and therapeutically tractable driver of CSF3R proximal and compound mutant leukemia, including ruxolitinib-resistant disease.","evidence":"Murine retroviral BMT models, expression profiling, MAPK biochemistry, and trametinib treatment","pmids":["28031554"],"confidence":"High","gaps":["Mechanism coupling receptor dimerization to Ksr1 induction not defined","Whether truncation-only disease shares MAPK dependence less clear"]},{"year":2019,"claim":"Showed that even the activating T618I receptor is constitutively phosphorylated and co-ubiquitinated with JAK2 and undergoes enhanced proteasomal turnover, reconciling constitutive signaling with low surface expression.","evidence":"Proteasome inhibition, immunoprecipitation, phosphotyrosine blotting, and surface expression assays","pmids":["31848046"],"confidence":"Medium","gaps":["E3 ligase responsible for T618I/JAK2 ubiquitination not identified","Single lab"]},{"year":2019,"claim":"Identified CSF3R splice variants and SRSF2 as a regulator of their ratio, with hypoproliferative V3 dampening JAK-STAT output unless rescued by V1.","evidence":"Digital PCR variant quantitation, proliferation/JAK-STAT assays, and SRSF2 knockout in KG-1 and CD34+ cells","pmids":["31462738"],"confidence":"Medium","gaps":["Direct SRSF2 binding to CSF3R pre-mRNA not shown here","In vivo consequences of altered V3/V1 ratio untested"]},{"year":2019,"claim":"Defined chromatin-level cooperation between CSF3R and partner lesions: SETBP1 mutations drive self-renewal via Myc programs, and CEBPA loss-of-function must precede CSF3R activation, blocking differentiation-associated enhancers.","evidence":"In vitro replating and in vivo mouse leukemia models with transcriptomic/epigenomic profiling and ordered-mutation epistasis","pmids":["35482940","31784538"],"confidence":"Medium","gaps":["Direct molecular link between CSF3R signaling and these chromatin programs not defined","Single lab per study"]},{"year":2020,"claim":"Extended G-CSFR function beyond granulopoiesis, showing it promotes immunosuppressive Treg/macrophage phenotypes that restrain antitumor cytotoxicity.","evidence":"G-CSFR knockout mice with adoptive transfer of T cells and macrophages and cytotoxicity/cytokine readouts","pmids":["33042110"],"confidence":"Medium","gaps":["Cell-intrinsic vs systemic G-CSFR effects not fully separated","Single lab"]},{"year":2021,"claim":"Implicated G-CSF/G-CSFR in hepatic metabolism via SOCS3-JAK-STAT3 signaling, linking the receptor to insulin resistance and steatosis.","evidence":"GCSF knockout mice on HFD, primary hepatocyte pathway analysis, and liver immune cell phenotyping","pmids":["33470903"],"confidence":"Medium","gaps":["Hepatocyte-autonomous CSF3R requirement not directly tested","Single lab"]},{"year":2022,"claim":"Established a direct splicing mechanism whereby SRSF2 P95H binds exon 17 ESEs to generate differentiation-impairing CSF3R Class III/IV isoforms, connecting a spliceosome mutation to aberrant receptor function.","evidence":"CSF3R minigene splicing assays, ESE deletion mutagenesis, and Csf3r-null mouse progenitor isoform add-back differentiation assays","pmids":["35941213"],"confidence":"High","gaps":["Signaling output of Class III/IV isoforms only partly characterized","Leukemic potential of isoforms in vivo not fully established"]},{"year":2023,"claim":"Identified post-transcriptional control of CSF3R: ALKBH5-mediated m6A demethylation stabilizes CSF3R mRNA to upregulate surface receptor and STAT3 signaling during bacterial infection.","evidence":"RIP-qPCR direct binding, ALKBH5 knockout mice, mRNA stability assays, surface flow cytometry, and STAT3 phosphorylation","pmids":["38114747"],"confidence":"High","gaps":["m6A site(s) on CSF3R mRNA not precisely mapped","Reader proteins linking m6A to stability not defined"]},{"year":2023,"claim":"Consolidated the glycosylation-guardrail model by mapping O-glycans (GalNAc, Gal-GalNAc) at WT Thr618 and showing the single domain containing residue 618 is sufficient for ligand-independent activity.","evidence":"Domain mapping, unbiased Ba/F3 mutational screen, and mass spectrometry glycan identification","pmids":["37116708"],"confidence":"High","gaps":["Glycan structures linking to dimerization control not structurally resolved","Glycosyltransferases responsible not identified"]},{"year":2024,"claim":"Revealed DUSP1 as a synthetic-lethal vulnerability of CSF3R leukemia, where MAPK-induced DUSP1 suppresses JNK-driven apoptosis, enabling a curative DUSP1+MEK inhibitor combination preclinically.","evidence":"Genetic Dusp1 deletion in murine CSF3R leukemia, BIM/P53/BCL2 signaling analysis, and combination drug treatment","pmids":["38531054"],"confidence":"Medium","gaps":["Single lab","Clinical translatability of DUSP1 inhibition not established"]},{"year":2025,"claim":"Showed ASXL1 truncation cooperates with CSF3R T621I to expand myeloid-biased HSCs and reprogram histone marks, with CSF3R mutation reversing expected H2AK119ub loss.","evidence":"Double-mutant mouse model with HSC phenotyping, ChIP-seq (H3K4me1, H2AK119ub), and transcriptomics","pmids":["39777477"],"confidence":"Medium","gaps":["Mechanism by which CSF3R signaling restores H2AK119ub not defined","Single lab"]},{"year":null,"claim":"How membrane-proximal glycosylation, receptor dimerization geometry, and compartmentalized JAK/STAT5 vs internalized STAT3/ERK signaling are integrated at structural and trafficking resolution remains unresolved, as do the specific E3 ligases and degrons controlling mutant receptor turnover.","evidence":"No timeline study provides a structural model of the ligand-free vs dimerized receptor or a unified trafficking-signaling map","pmids":[],"confidence":"Low","gaps":["No structural model of glycosylation-controlled dimerization","E3 ligase for T618I/JAK2 ubiquitination unidentified","Endosomal scaffolds for STAT3/ERK activation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,14]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[12,22]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma 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JAGN1","url":"https://www.omim.org/entry/616012"},{"mim_id":"610738","title":"NEUTROPENIA, SEVERE CONGENITAL, 3, AUTOSOMAL RECESSIVE; SCN3","url":"https://www.omim.org/entry/610738"},{"mim_id":"608764","title":"NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; NAMPT","url":"https://www.omim.org/entry/608764"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":183.7},{"tissue":"lung","ntpm":134.4},{"tissue":"lymphoid 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In contrast, truncation mutations induce receptor overexpression and ligand hypersensitivity by removing endocytosis/degradation motifs. Combining both mutation types on the same allele leads to enhanced cellular transformation compared to either alone.\",\n      \"method\": \"Mutagenesis of O-glycosylation sites, receptor dimerization assays, cell transformation assays (Ba/F3), receptor expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, dimerization assays, and transformation assays in a single rigorous study\",\n      \"pmids\": [\"24403076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A critical internalization domain in the G-CSFR cytoplasmic region is deleted in truncation mutants found in SCN/AML patients; deletion of this domain results in impaired ligand internalization, defective receptor downmodulation, and enhanced growth signaling, explaining the dominant-negative hypersensitivity phenotype.\",\n      \"method\": \"Ligand internalization assays, receptor downmodulation studies, growth signaling assays in transfected cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional assays with defined receptor mutants demonstrating mechanistic basis of dominant-negative phenotype\",\n      \"pmids\": [\"9885205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Expression of truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level dependent on exogenous G-CSF, mediated through increased G-CSF-induced proliferation and enhanced Stat5 phosphorylation. The proliferative advantage is abrogated in myeloid progenitors lacking both Stat5A and Stat5B, and is reduced in mice expressing a truncated Csf3r engineered to have impaired Stat5 activation.\",\n      \"method\": \"Murine bone marrow transplantation, Stat5 knockout epistasis, phosphorylation assays, Stat5 target gene transcription analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis with Stat5 knockout plus multiple in vivo models, replicated across multiple approaches in one study\",\n      \"pmids\": [\"18292815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The CSF3R T618I mutation is sufficient to drive a lethal myeloproliferative disorder (overproduction of granulocytes, spleen/liver infiltration) in a murine bone marrow transplantation model, and disease is sensitive to pharmacologic JAK1/2 inhibition with ruxolitinib (reduced WBC, reduced spleen weight).\",\n      \"method\": \"Murine bone marrow transplantation model, ruxolitinib treatment, hematologic and histologic analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo reconstitution model with defined mutation plus pharmacological validation\",\n      \"pmids\": [\"24081659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A T617N CSF3R transmembrane domain mutation energetically favors receptor dimerization, leading to constitutive receptor activation and hypersensitivity to G-CSF for proliferation and differentiation, causing hereditary chronic neutrophilia.\",\n      \"method\": \"Structural/energetic analysis of transmembrane dimerization, xenotransplantation and syngeneic mouse bone marrow engraftment assays, family clinical study\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo engraftment models plus transmembrane dimerization analysis, single lab\",\n      \"pmids\": [\"19620628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The G-CSFR is constitutively ubiquitinated, with ubiquitination increasing after ligand binding. Abrogation of ubiquitin attachment at K762 (the residue deleted in SCN/AML truncation mutants) impairs ligand-induced internalization, prolongs Stat5 and Akt activation after G-CSF withdrawal, and enhances proliferation and survival.\",\n      \"method\": \"Site-directed mutagenesis (K762R), ubiquitination assays, internalization assays, signaling (Stat5, Akt phosphorylation), proliferation/survival assays in transfected cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with multiple orthogonal functional assays (ubiquitination, internalization, signaling, proliferation) in one study\",\n      \"pmids\": [\"18923646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The ubiquitin/proteasome system is required for G-CSFR internalization and degradation: in cells with a temperature-sensitive E1 ubiquitin-activating enzyme, ligand-induced receptor internalization is inhibited. In primary human neutrophils, proteasome inhibition (but not lysosome inhibition) blocks internalization/degradation of the activated G-CSFR.\",\n      \"method\": \"Temperature-sensitive E1 ubiquitin-activating enzyme cell lines, chloroquine/MG132 pharmacological inhibition, flow cytometry/western blot in primary neutrophils\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal approaches (genetic E1 loss-of-function, pharmacological inhibition) in both cell lines and primary cells\",\n      \"pmids\": [\"18554923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbw7 (an SCF E3 ubiquitin ligase substrate-recognition subunit) physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation; Fbw7-mediated G-CSFR downregulation reduces STAT3 phosphorylation. Fbw7 and GSK3β are interdependent in targeting G-CSFR for degradation—neither alone can degrade G-CSFR when the other is knocked down.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, knockdown experiments, STAT3 phosphorylation assays, granulocytic differentiation assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"23820376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"E6AP (an E3 ubiquitin ligase) physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation, reducing STAT3 phosphorylation and inhibiting granulocytic differentiation. E6AP knockdown restores G-CSFR expression and signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, knockdown experiments, STAT3 phosphorylation and differentiation assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional knockdown, single lab\",\n      \"pmids\": [\"28578910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Neutrophil elastase (NE) proteolytically cleaves G-CSFR at its amino-terminus on human PMN in a time-dependent manner, releasing cleavage fragments into conditioned media and reducing receptor surface expression. NE treatment of bone marrow progenitors also inhibits granulocyte-macrophage colony formation (CFU-GM).\",\n      \"method\": \"Flow cytometry, western blot, conditioned media analysis for cleavage fragments, CFU-GM colony assay\",\n      \"journal\": \"Journal of inflammation (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of proteolytic cleavage plus functional colony assay, single lab\",\n      \"pmids\": [\"20205821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A homozygous Arg308Cys CSF3R missense mutation causes perturbed N-glycosylation and aberrant (reduced) surface localization of the receptor, resulting in SCN with full myeloid bone marrow maturation but no response to recombinant G-CSF.\",\n      \"method\": \"Genetic analysis of two SCN families, functional analysis of surface expression and N-glycosylation, clinical G-CSF response testing\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mutation with defined molecular consequence (glycosylation/surface expression defect) plus clinical phenotype, two unrelated families\",\n      \"pmids\": [\"24753537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A point mutation at the SD splice donor site in the G-CSFR gene in a case of AML leads to overexpression of a novel isoform (SD) lacking the distal C-terminal cytoplasmic maturation-signaling region; the SD isoform has high G-CSF affinity but is scarcely capable of activating JAK2 and fails to transduce growth signals in BAF3 cells.\",\n      \"method\": \"Splice site mutation identification, G-CSF binding assay (affinity), JAK2 activation assay, BAF3 growth signaling assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of isoform with JAK2 activation and growth signaling assays, single study\",\n      \"pmids\": [\"7531515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSF3R T618I mutations cause constitutive tyrosine phosphorylation of the O-glycosylated receptor form and constitutive ubiquitination of both the mutant receptor and JAK2; the T618I receptor undergoes enhanced spontaneous internalization and degradation (proteasome-dependent), resulting in markedly decreased surface expression.\",\n      \"method\": \"Proteasome inhibitor treatment, immunoprecipitation, phosphotyrosine blotting, surface expression analysis in transfected cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical approaches (phosphorylation, ubiquitination, internalization assays), single lab\",\n      \"pmids\": [\"31848046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Using a cellular transformation screen in Ba/F3 cells, four distinct mechanisms of CSF3R gain-of-function mutations were identified: (1) cysteine/disulfide bond-mediated dimerization (S581C); (2) polar substitution at transmembrane helix dimer interface (T640); (3) increased internalization mimicking low G-CSF dose (E524 substitutions); (4) hydrophobic substitutions in membrane-proximal residues (T612, T615, T618). Additionally, CSF3R-induced STAT3 and ERK activations require receptor internalization, whereas STAT5 activation occurs at the cell surface.\",\n      \"method\": \"Ba/F3 cellular transformation screen, sequencing of outgrowth clones, receptor localization studies, signaling assays (STAT3, STAT5, ERK) with internalization inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — unbiased functional screen with mechanistic follow-up including localization studies and pathway-specific signaling dissection, multiple orthogonal methods\",\n      \"pmids\": [\"29572350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CSF3R distal cytoplasmic truncation mutations (Q793–Q823) have leukemogenic potential due to markedly decreased receptor degradation, attributed to loss of a de-phosphorylation domain (residues N818–F836). All truncations prior to Q823 increase expression of the higher-molecular-weight (higher-glycosylated) CSF3R band, which is essential for surface expression and oncogenic potential. Sufficient STAT5 activation is required for oncogenic potential.\",\n      \"method\": \"Ba/F3 transformation assays, receptor degradation assays, STAT5 activation assays, western blot for receptor glycoforms\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transformation assays plus mechanistic receptor degradation studies, single lab\",\n      \"pmids\": [\"28439110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CSF3R proximal mutations alone are leukemogenic (90-day latency in mice) while truncation mutations alone cannot induce leukemia; compound mutations (proximal + truncation on same allele) are leukemogenic with shorter latency (23 days). Upregulation of MAPK adaptor Ksr1 and enhanced MAPK signaling are critical for leukemogenesis by CSF3R proximal and compound mutants; MEK1/2 inhibition by trametinib suppresses leukemia from both mutation types including ruxolitinib-resistant compound mutations.\",\n      \"method\": \"Murine retroviral bone marrow transplantation models, whole-genome expression profiling, biochemical MAPK assays, trametinib pharmacological inhibition\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse models with epistatic analysis, expression profiling, and pharmacological validation, multiple orthogonal approaches\",\n      \"pmids\": [\"28031554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A W341C extracellular domain CSF3R mutation transforms cells via cysteine-mediated intermolecular disulfide bonds leading to receptor dimerization. Disruption of original cysteine pairs in the CSF3R extracellular domain results in either gain- or loss-of-function depending on the specific pair disrupted.\",\n      \"method\": \"Ba/F3 transformation assays, disulfide bond/dimerization analysis, JAK inhibitor sensitivity testing\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transformation assay with biochemical dimerization analysis, single lab\",\n      \"pmids\": [\"28652245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The N610 residue of CSF3R is part of a consensus N-linked glycosylation motif and is the primary site of sialylation; mass spectrometry confirmed complex N-glycans at this site. N610 mutations prevent membrane-proximal N-glycosylation and drive ligand-independent cellular expansion, demonstrating that membrane-proximal N-linked glycosylation is critical for maintaining ligand dependence of the receptor.\",\n      \"method\": \"Mass spectrometry glycan mapping, mutagenesis of N610, proliferation/transformation assays, JAK inhibitor sensitivity testing\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry glycan confirmation plus mutagenesis plus functional transformation assay, single rigorous study with orthogonal methods\",\n      \"pmids\": [\"30348809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Unbiased mutational screening confirmed that activating CSF3R mutations are enriched at glycosylated residues (asparagine, threonine, serine); mass spectrometry confirmed glycosylation at multiple CSF3R residues including GalNAc and Gal-GalNAc O-glycans at WT Thr618. The single CSF3R domain containing residue 618 is sufficient for ligand-independent activity.\",\n      \"method\": \"Protein domain mapping, unbiased mutational screen in Ba/F3 cells, mass spectrometry glycan identification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry glycan mapping plus domain mapping plus mutational screen, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37116708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"G-CSF dose-independently downregulates its own receptor (CD114) on neutrophil surfaces by ~75% in humans and induces neutrophil degranulation (CD11b upregulation) and gelatinase B release (~10-fold increase in plasma); endotoxin (LPS) also downmodulates G-CSFR on neutrophils in vivo in humans.\",\n      \"method\": \"Randomized controlled human endotoxemia study and G-CSF infusion study with flow cytometry for receptor expression, plasma gelatinase B measurement\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo human experiments with flow cytometry receptor quantification and functional readouts\",\n      \"pmids\": [\"11091218\", \"10882621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"G-CSF receptor-mediated clearance is an important mechanism for plasma clearance of both filgrastim and pegfilgrastim: G-CSFR knockout mice show significantly greater AUC, longer half-life, longer MRT, and lower clearance compared to wild-type mice for both drugs at both doses tested.\",\n      \"method\": \"G-CSFR knockout mice vs. wild-type pharmacokinetic comparison with ELISA-based plasma drug measurement\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout model with defined pharmacokinetic readout, single study\",\n      \"pmids\": [\"15082029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LRG (leucine-rich alpha2-glycoprotein) expression is induced by G-CSF in myeloid cells; stable LRG expression accelerates G-CSF-mediated neutrophil differentiation and CD11b induction correlating with increased phospho-STAT3, but this acceleration is not seen in cells expressing a chimeric EpoR/G-CSFR (EpoR extracellular + G-CSFR transmembrane/cytoplasmic domains) stimulated with Epo, suggesting LRG acts through G-CSFR-specific extracellular/ligand-binding signals.\",\n      \"method\": \"Stable LRG transfection in 32Dcl3 cells, chimeric EpoR/G-CSFR signaling experiments, STAT3 phosphorylation, CD11b flow cytometry\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric receptor epistasis plus stable transfection with pathway readout, single lab\",\n      \"pmids\": [\"18272588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A truncated G-CSFR mutant (d715, from SCN patient) inhibits G-CSF-induced NE expression in a dominant-negative manner and suppresses unfolded protein response and apoptosis induced by the SCN-derived NE G185R mutant, associated with sustained AKT and STAT5 activation and augmented BCL-XL expression.\",\n      \"method\": \"Dominant-negative expression of G-CSFR d715, NE expression assays, UPR/apoptosis assays, AKT/STAT5 phosphorylation, BCL-XL western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling readouts with defined mutant receptor, single lab\",\n      \"pmids\": [\"28073911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Three CSF3R mRNA splice variants exist in hematopoietic cells (V1=wild-type, V3, V4). V3 expression alone confers a hypoproliferative phenotype with defective JAK-STAT activation; coexpression of V1 with V3 rescues proliferative responses. SRSF2 mutations increase the V3/V1 ratio; SRSF2 knockout decreases the V3/V1 ratio.\",\n      \"method\": \"Digital PCR splice variant quantitation, functional proliferation assays, JAK-STAT activation assays, SRSF2 knockout in KG-1 and CD34+ cells\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of splice variant with pathway readout plus genetic SRSF2 manipulation, single lab\",\n      \"pmids\": [\"31462738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF2 P95H mutation promotes increased expression of CSF3R Class IV splice isoform by binding to exonic splicing enhancer (ESE) sequences in CSF3R exon 17; deletion of either ESE motif decreases Class IV transcripts. Class IV isoform add-back in Csf3r-null mouse progenitors increases granulocyte progenitors with impaired neutrophil differentiation. Class III isoform produces dysmorphic neutrophils.\",\n      \"method\": \"In vitro splicing assays with CSF3R minigene, ESE deletion mutagenesis, Csf3r-null mouse progenitor reconstitution, CD34+ cell G-CSF differentiation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro splicing assay with mutagenesis plus in vivo reconstitution in null cells, multiple orthogonal methods\",\n      \"pmids\": [\"35941213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cooperating CSF3R and RUNX1 mutations co-occur in the same malignant clone in CN/AML patients. Hematopoietic CD34+ cells coexpressing mutated RUNX1 and mutated CSF3R show elevated G-CSF-induced proliferation with diminished myeloid differentiation.\",\n      \"method\": \"Single-cell analysis confirming co-occurrence in same clone, functional G-CSF proliferation and differentiation assays of CD34+ cells coexpressing both mutants\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell clonal analysis plus functional CD34+ cell assays, single lab\",\n      \"pmids\": [\"24523240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Truncated G-CSFR cooperates with PML-RARα to induce AML in mice in a G-CSF-dependent fashion, significantly shortening AML latency, demonstrating a causal role for CSF3R truncation mutations in leukemic transformation.\",\n      \"method\": \"Murine retroviral co-expression bone marrow transplantation model, G-CSF dependency testing, hematologic/histologic AML characterization\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo murine leukemia cooperation model with G-CSF dependency, single lab\",\n      \"pmids\": [\"21911095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALKBH5 (m6A RNA demethylase) directly binds CSF3R mRNA and erases m6A methylation on it, increasing CSF3R mRNA stability and protein expression, thereby upregulating cell surface G-CSFR expression and downstream STAT3 signaling in neutrophils during bacterial infection.\",\n      \"method\": \"RIP-qPCR (direct ALKBH5-CSF3R mRNA binding), ALKBH5 knockout mice, mRNA stability assays, surface G-CSFR flow cytometry, STAT3 phosphorylation assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP-qPCR confirmed direct binding, knockout model, multiple functional readouts including mRNA stability, surface expression, and signaling\",\n      \"pmids\": [\"38114747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"G-CSF/G-CSFR signaling promotes an IL-10-producing, FoxP3-expressing inhibitory Treg phenotype in both CD4+ and CD8+ T cells; G-CSFR-/- T cells exhibit increased IFNγ and IL-17A production and greater cytotoxic activity against tumors. Adoptive transfer of G-CSFR-/- macrophages into tumor-bearing mice also shows higher NOS2/NO production and greater tumor cytotoxicity vs. WT macrophages.\",\n      \"method\": \"G-CSFR knockout mice, adoptive transfer of WT vs G-CSFR-/- T cells and macrophages, cytokine multiplex, flow cytometry, in vitro/in vivo cytotoxicity assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer experiments with defined cellular phenotyping and functional readouts, single lab\",\n      \"pmids\": [\"33042110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GCSF binds to GCSFR and activates the SOCS3-JAK-STAT3 signaling pathway in hepatocytes, and GCSF deficiency alleviates HFD-induced insulin resistance and hepatic steatosis in mice.\",\n      \"method\": \"GCSF knockout mice on HFD, primary hepatocyte treatment, SOCS3/JAK/STAT3 pathway analysis, liver immune cell flow cytometry\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus in vitro hepatocyte mechanistic pathway analysis, single lab\",\n      \"pmids\": [\"33470903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Enhanced MAPK signaling in CSF3R-driven leukemia upregulates DUSP1 expression to suppress apoptosis; genetic deletion of Dusp1 confers synthetic lethality to CSF3R-induced leukemia in mice. DUSP1 depletion activates JNK1/2, inducing BIM and P53 expression and suppressing BCL2 to trigger selective apoptosis in leukemic cells. Combined BCI (DUSP1 inhibitor) + MEK inhibitor cures CSF3R-induced leukemia in preclinical mice.\",\n      \"method\": \"Genetic Dusp1 deletion in murine CSF3R leukemia model, BIM/P53/BCL2 signaling analysis, pharmacological combination treatment in vivo\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout demonstrating synthetic lethality plus mechanistic signaling analysis, single lab\",\n      \"pmids\": [\"38531054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Src-family kinase Lyn and non-Src kinase Syk associate with the G-CSFR in neutrophils from SCN patients expressing truncated G-CSFR; Syk association is retained because the Syk binding motif (aa 727–747) is upstream of the truncation sites, confirming normal G-CSFR is also expressed in these patients.\",\n      \"method\": \"Co-immunoprecipitation of Lyn and Syk with G-CSFR in neutrophils\",\n      \"journal\": \"International journal of hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP experiment in patient neutrophils, no functional follow-up\",\n      \"pmids\": [\"10643150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The T618I CSF3R mutation retains O-glycosylation but the O-glycosylated T618I receptor form is constitutively tyrosine phosphorylated and constitutively ubiquitinated along with JAK2; proteasome inhibition markedly increases T618I surface expression, indicating enhanced proteasome-dependent receptor turnover as a mechanism of decreased T618I surface expression.\",\n      \"method\": \"Proteasome inhibitor assays, immunoprecipitation/phosphotyrosine blotting, ubiquitination assays in transfected cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays establishing constitutive phosphorylation and ubiquitination mechanism, single lab\",\n      \"pmids\": [\"31848046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SETBP1 mutations promote self-renewal of CSF3R-mutated hematopoietic progenitors in vitro, prevent terminal differentiation, and accelerate leukemia progression in vivo through upregulation of Myc and Myc target gene expression programs (reversible by LSD1 inhibitors).\",\n      \"method\": \"In vitro progenitor colony replating assays, in vivo mouse leukemia models, transcriptomic and epigenomic profiling, LSD1 inhibitor treatment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo models with transcriptomic/epigenomic mechanistic characterization, single lab\",\n      \"pmids\": [\"35482940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Activating CSF3R mutations cooperate with CEBPA loss-of-function mutations at the level of myeloid lineage enhancers: mutant CEBPA prevents activation of a subset of differentiation-associated enhancers, and CEBPA mutations must occur as the initial event before CSF3R mutations for AML initiation.\",\n      \"method\": \"Murine AML models with defined mutation order, chromatin profiling (enhancer activation analysis), epistasis experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo epistasis with enhancer profiling, mechanistic at chromatin level, single lab\",\n      \"pmids\": [\"31784538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dual Asxl1Y588X and Csf3rT621I mutations cause expansion of myeloid-biased long-term HSCs and enhanced neutrophil differentiation with activation of inflammatory pathways. Asxl1 truncation enhances CSF3RT618I-driven neutrophil differentiation and increases H3K4me1 at neutrophil-associated enhancers. The expected decrease in H2AK119ub in Asxl1-mutant cells is reversed when CSF3R is also mutated.\",\n      \"method\": \"Double-mutant mouse model, HSC flow cytometric analysis, ChIP-seq (H3K4me1, H2AK119ub), transcriptomic profiling, myeloid differentiation assays\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-mutant mouse model with epigenomic characterization, single lab\",\n      \"pmids\": [\"39777477\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSF3R encodes the G-CSF receptor, a cytokine receptor whose ligand-dependent signaling is regulated by O- and N-linked glycosylation (which maintain ligand dependence by preventing constitutive dimerization), ubiquitin/proteasome-mediated internalization and degradation (with E3 ligases Fbw7, E6AP, and GSK3β targeting K762), and post-activation downregulation via NE-mediated ectodomain cleavage or receptor internalization; oncogenic mutations cluster into two mechanistically distinct classes—membrane-proximal mutations (e.g., T618I) that abolish O-glycosylation and promote constitutive receptor dimerization and ligand-independent JAK/STAT and MAPK signaling, and cytoplasmic truncation mutations that delete internalization and ubiquitination motifs to cause receptor overexpression and G-CSF hypersensitivity with preferential SRC-family signaling—while cooperating mutations in RUNX1, CEBPA, SETBP1, or ASXL1 further promote leukemic transformation through distinct chromatin and transcriptional mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CSF3R encodes the granulocyte colony-stimulating factor receptor (G-CSFR/CD114), a cytokine receptor that couples G-CSF binding to JAK/STAT5, STAT3, and MAPK signaling to drive granulocytic proliferation and differentiation [#3, #14, #16]. Ligand dependence is enforced by membrane-proximal glycosylation: O-linked glycosylation at Thr-615/Thr-618 and N-linked glycosylation at Asn-610 prevent spontaneous dimerization, and unbiased mutational screens confirm that activating mutations are enriched at these glycosylated serine, threonine, and asparagine residues [#1, #18, #19]. Receptor output is constrained by ubiquitin/proteasome-dependent internalization and degradation, which requires the ubiquitin-activating enzyme E1 and is targeted by the E3 ligases Fbw7 (interdependently with GSK3\\u03b2) and E6AP, with ubiquitination at Lys-762 limiting STAT5/STAT3/Akt signaling; loss of these C-terminal motifs underlies receptor overexpression in disease [#6, #7, #8, #9]. Oncogenic mutations fall into two mechanistically distinct classes: membrane-proximal mutations such as T618I that abolish glycosylation, promote constitutive dimerization and ligand-independent JAK/STAT signaling, and are leukemogenic alone via enhanced MAPK signaling; and cytoplasmic truncation mutations that delete internalization/ubiquitination motifs to cause G-CSF hypersensitivity and preferential SRC-family-TNK2 signaling, transforming only in cooperation with other lesions [#0, #1, #2, #16]. Membrane-proximal mutations confer ruxolitinib sensitivity in vivo, while MAPK dependence renders both classes sensitive to MEK inhibition, and DUSP1 is a synthetic-lethal vulnerability of CSF3R-driven leukemia [#4, #16, #31]. Truncation- and proximal-mutant disease is further driven by cooperating lesions in RUNX1, CEBPA, SETBP1, ASXL1, and by SRSF2-directed missplicing of CSF3R that generates differentiation-impairing isoforms [#16, #25, #26, #34, #35, #36]. Inherited CSF3R missense and transmembrane mutations cause both hereditary chronic neutrophilia (gain-of-function dimerization) and severe congenital neutropenia (loss of surface expression) [#5, #11].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that the distal cytoplasmic C-terminus is required for G-CSFR to transduce growth signals, defining the maturation-signaling region whose loss appears in disease isoforms.\",\n      \"evidence\": \"AML-derived SD splice isoform lacking the distal C-terminus assayed for G-CSF binding, JAK2 activation, and BAF3 growth signaling\",\n      \"pmids\": [\"7531515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single isoform from one case\", \"Did not define which residues mediate JAK2 coupling\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified a cytoplasmic internalization domain deleted in SCN/AML truncation mutants as the mechanistic basis of defective receptor downmodulation and hypersensitive growth signaling.\",\n      \"evidence\": \"Ligand internalization, receptor downmodulation, and growth assays with defined truncation mutants in transfected cells\",\n      \"pmids\": [\"9885205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the E3 ligases or ubiquitination sites involved\", \"Mechanism of dominant-negative behavior over WT receptor not fully resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined ubiquitin/proteasome-dependent control of receptor turnover, showing constitutive and ligand-enhanced ubiquitination at K762 limits the duration of STAT5/Akt signaling.\",\n      \"evidence\": \"K762R mutagenesis, ubiquitination/internalization/signaling assays, temperature-sensitive E1 cells, and proteasome inhibition in primary neutrophils\",\n      \"pmids\": [\"18923646\", \"18554923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligases not yet identified in these studies\", \"Relationship between K762 ubiquitination and lysosomal vs proteasomal routing partly unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated in vivo that truncated G-CSFR confers a G-CSF-dependent HSC clonal advantage operating through STAT5, linking receptor truncation to a defined downstream effector.\",\n      \"evidence\": \"Murine bone marrow transplantation with Stat5A/B knockout epistasis and STAT5-impaired truncated receptor\",\n      \"pmids\": [\"18292815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address transformation to overt leukemia by truncation alone\", \"STAT5 target genes driving proliferation not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed a transmembrane CSF3R mutation can energetically favor dimerization and cause hereditary chronic neutrophilia, establishing constitutive dimerization as a disease mechanism.\",\n      \"evidence\": \"Transmembrane dimerization energetics, mouse engraftment, and family clinical study of T617N\",\n      \"pmids\": [\"19620628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab/family\", \"Whether T617N predisposes to leukemic transformation not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified neutrophil elastase as a post-activation negative regulator that cleaves the G-CSFR ectodomain to reduce surface expression and constrain granulocyte colony formation.\",\n      \"evidence\": \"NE treatment of human PMN with flow cytometry, cleavage-fragment western blot, and CFU-GM assays\",\n      \"pmids\": [\"20205821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site not precisely mapped\", \"Physiological contribution relative to ubiquitin-mediated turnover unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the two-class model of CSF3R oncogenic mutations with distinct kinase dependencies and showed T618I alone drives a JAK-inhibitor-sensitive myeloproliferative disorder.\",\n      \"evidence\": \"Inhibitor panels, siRNA screens, transformation assays on patient cells, and a ruxolitinib-treated T618I mouse model\",\n      \"pmids\": [\"23656643\", \"24081659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of membrane-proximal activation not yet defined here\", \"Truncation-class transformation requirements for cooperating lesions not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified Fbw7 as an E3 ligase that, interdependently with GSK3\\u03b2, ubiquitinates G-CSFR to dampen STAT3 signaling and granulocytic differentiation.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination, knockdown, and STAT3/differentiation assays\",\n      \"pmids\": [\"23820376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Degron sequence recognized by Fbw7 on G-CSFR not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Pinpointed loss of O-glycosylation at Thr-615/Thr-618 as the molecular cause of T618I-driven ligand-independent dimerization, and showed compound proximal+truncation alleles enhance transformation.\",\n      \"evidence\": \"O-glycosylation site mutagenesis, dimerization, and Ba/F3 transformation assays\",\n      \"pmids\": [\"24403076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve N-linked contribution\", \"Structural basis of glycosylation-controlled dimerization not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a loss-of-function CSF3R disease axis: an Arg308Cys mutation perturbs N-glycosylation and reduces surface localization, causing SCN unresponsive to G-CSF.\",\n      \"evidence\": \"Genetic analysis of two SCN families with surface expression, N-glycosylation, and clinical G-CSF response testing\",\n      \"pmids\": [\"24753537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two families only\", \"Trafficking step impaired by the mutation not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CSF3R and RUNX1 mutations co-occur in the same clone and cooperatively enhance proliferation while blocking differentiation, framing CSF3R as a cooperating lesion in CN/AML.\",\n      \"evidence\": \"Single-cell clonal analysis and functional CD34+ co-expression proliferation/differentiation assays\",\n      \"pmids\": [\"24523240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RUNX1/CSF3R synergy at transcriptional level not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded the negative-regulator landscape by identifying E6AP as a second E3 ligase degrading G-CSFR and dampening STAT3-driven differentiation.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination, knockdown, and STAT3/differentiation assays\",\n      \"pmids\": [\"28578910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Hierarchy/overlap with Fbw7-mediated degradation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the leukemogenic mechanism of distal truncations as loss of a de-phosphorylation domain causing reduced degradation, and tied oncogenicity to the higher-glycosylated surface receptor form and sufficient STAT5 activation.\",\n      \"evidence\": \"Ba/F3 transformation, receptor degradation, glycoform western blots, and STAT5 assays\",\n      \"pmids\": [\"28439110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the phosphatase recruited to the deleted domain not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that extracellular cysteine substitutions (W341C) transform via disulfide-mediated dimerization, broadening the mechanisms of ligand-independent activation.\",\n      \"evidence\": \"Ba/F3 transformation, disulfide/dimerization analysis, and JAK inhibitor sensitivity testing\",\n      \"pmids\": [\"28652245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Frequency of extracellular-domain mutations in patients not assessed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed a truncated G-CSFR can act dominant-negatively to suppress NE-induced UPR and apoptosis via sustained AKT/STAT5 and BCL-XL, linking receptor truncation to survival of SCN-derived clones.\",\n      \"evidence\": \"Dominant-negative d715 expression with UPR/apoptosis and AKT/STAT5/BCL-XL readouts\",\n      \"pmids\": [\"28073911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct contribution to leukemic progression in vivo not tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided an unbiased mechanistic taxonomy of CSF3R gain-of-function mutations and showed that STAT3/ERK activation requires receptor internalization whereas STAT5 acts at the surface, spatially partitioning downstream signaling.\",\n      \"evidence\": \"Ba/F3 transformation screen, outgrowth sequencing, localization, and pathway-specific signaling with internalization inhibitors\",\n      \"pmids\": [\"29572350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal scaffolds mediating STAT3/ERK activation not identified\", \"In vivo relevance of compartmentalized signaling not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified Asn-610 as the primary N-linked sialylation site whose loss drives ligand-independent expansion, establishing membrane-proximal N-glycosylation as a second glycan-based guardrail of ligand dependence.\",\n      \"evidence\": \"Mass spectrometry glycan mapping, N610 mutagenesis, transformation, and JAK inhibitor sensitivity\",\n      \"pmids\": [\"30348809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between N610 and O-glycosylation in dimerization control not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined MAPK signaling, via Ksr1 upregulation, as a critical and therapeutically tractable driver of CSF3R proximal and compound mutant leukemia, including ruxolitinib-resistant disease.\",\n      \"evidence\": \"Murine retroviral BMT models, expression profiling, MAPK biochemistry, and trametinib treatment\",\n      \"pmids\": [\"28031554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling receptor dimerization to Ksr1 induction not defined\", \"Whether truncation-only disease shares MAPK dependence less clear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that even the activating T618I receptor is constitutively phosphorylated and co-ubiquitinated with JAK2 and undergoes enhanced proteasomal turnover, reconciling constitutive signaling with low surface expression.\",\n      \"evidence\": \"Proteasome inhibition, immunoprecipitation, phosphotyrosine blotting, and surface expression assays\",\n      \"pmids\": [\"31848046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for T618I/JAK2 ubiquitination not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified CSF3R splice variants and SRSF2 as a regulator of their ratio, with hypoproliferative V3 dampening JAK-STAT output unless rescued by V1.\",\n      \"evidence\": \"Digital PCR variant quantitation, proliferation/JAK-STAT assays, and SRSF2 knockout in KG-1 and CD34+ cells\",\n      \"pmids\": [\"31462738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SRSF2 binding to CSF3R pre-mRNA not shown here\", \"In vivo consequences of altered V3/V1 ratio untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined chromatin-level cooperation between CSF3R and partner lesions: SETBP1 mutations drive self-renewal via Myc programs, and CEBPA loss-of-function must precede CSF3R activation, blocking differentiation-associated enhancers.\",\n      \"evidence\": \"In vitro replating and in vivo mouse leukemia models with transcriptomic/epigenomic profiling and ordered-mutation epistasis\",\n      \"pmids\": [\"35482940\", \"31784538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CSF3R signaling and these chromatin programs not defined\", \"Single lab per study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended G-CSFR function beyond granulopoiesis, showing it promotes immunosuppressive Treg/macrophage phenotypes that restrain antitumor cytotoxicity.\",\n      \"evidence\": \"G-CSFR knockout mice with adoptive transfer of T cells and macrophages and cytotoxicity/cytokine readouts\",\n      \"pmids\": [\"33042110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic vs systemic G-CSFR effects not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated G-CSF/G-CSFR in hepatic metabolism via SOCS3-JAK-STAT3 signaling, linking the receptor to insulin resistance and steatosis.\",\n      \"evidence\": \"GCSF knockout mice on HFD, primary hepatocyte pathway analysis, and liver immune cell phenotyping\",\n      \"pmids\": [\"33470903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hepatocyte-autonomous CSF3R requirement not directly tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a direct splicing mechanism whereby SRSF2 P95H binds exon 17 ESEs to generate differentiation-impairing CSF3R Class III/IV isoforms, connecting a spliceosome mutation to aberrant receptor function.\",\n      \"evidence\": \"CSF3R minigene splicing assays, ESE deletion mutagenesis, and Csf3r-null mouse progenitor isoform add-back differentiation assays\",\n      \"pmids\": [\"35941213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling output of Class III/IV isoforms only partly characterized\", \"Leukemic potential of isoforms in vivo not fully established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified post-transcriptional control of CSF3R: ALKBH5-mediated m6A demethylation stabilizes CSF3R mRNA to upregulate surface receptor and STAT3 signaling during bacterial infection.\",\n      \"evidence\": \"RIP-qPCR direct binding, ALKBH5 knockout mice, mRNA stability assays, surface flow cytometry, and STAT3 phosphorylation\",\n      \"pmids\": [\"38114747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m6A site(s) on CSF3R mRNA not precisely mapped\", \"Reader proteins linking m6A to stability not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Consolidated the glycosylation-guardrail model by mapping O-glycans (GalNAc, Gal-GalNAc) at WT Thr618 and showing the single domain containing residue 618 is sufficient for ligand-independent activity.\",\n      \"evidence\": \"Domain mapping, unbiased Ba/F3 mutational screen, and mass spectrometry glycan identification\",\n      \"pmids\": [\"37116708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan structures linking to dimerization control not structurally resolved\", \"Glycosyltransferases responsible not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed DUSP1 as a synthetic-lethal vulnerability of CSF3R leukemia, where MAPK-induced DUSP1 suppresses JNK-driven apoptosis, enabling a curative DUSP1+MEK inhibitor combination preclinically.\",\n      \"evidence\": \"Genetic Dusp1 deletion in murine CSF3R leukemia, BIM/P53/BCL2 signaling analysis, and combination drug treatment\",\n      \"pmids\": [\"38531054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Clinical translatability of DUSP1 inhibition not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed ASXL1 truncation cooperates with CSF3R T621I to expand myeloid-biased HSCs and reprogram histone marks, with CSF3R mutation reversing expected H2AK119ub loss.\",\n      \"evidence\": \"Double-mutant mouse model with HSC phenotyping, ChIP-seq (H3K4me1, H2AK119ub), and transcriptomics\",\n      \"pmids\": [\"39777477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CSF3R signaling restores H2AK119ub not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How membrane-proximal glycosylation, receptor dimerization geometry, and compartmentalized JAK/STAT5 vs internalized STAT3/ERK signaling are integrated at structural and trafficking resolution remains unresolved, as do the specific E3 ligases and degrons controlling mutant receptor turnover.\",\n      \"evidence\": \"No timeline study provides a structural model of the ligand-free vs dimerized receptor or a unified trafficking-signaling map\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of glycosylation-controlled dimerization\", \"E3 ligase for T618I/JAK2 ubiquitination unidentified\", \"Endosomal scaffolds for STAT3/ERK activation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [12, 22]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 11, 13, 18, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 14, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [20, 28, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4, 16, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CSF3\", \"JAK2\", \"Fbw7\", \"GSK3B\", \"E6AP\", \"LYN\", \"SYK\", \"ALKBH5\"]\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}