{"gene":"FIP1L1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2003,"finding":"An interstitial deletion on chromosome 4q12 fuses FIP1L1 to PDGFRA, creating a constitutively activated tyrosine kinase (FIP1L1-PDGFRα) that transforms hematopoietic cells. The fusion kinase is inhibited by imatinib (IC50 ~3.2 nM). Resistance is conferred by a T674I point mutation in the PDGFRα kinase domain.","method":"Chromosomal analysis, RT-PCR, cell transformation assay (Ba/F3), in vitro kinase inhibition assay","journal":"The New England Journal of Medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — constitutive kinase activity demonstrated in cell transformation assay, IC50 measured in vitro, resistance mutation confirmed at relapse, replicated across multiple subsequent studies","pmids":["12660384"],"is_preprint":false},{"year":2003,"finding":"PKC412 (midostaurin) inhibits FIP1L1-PDGFRα, including the imatinib-resistant T674I mutant, in a murine bone marrow transplant model of FIP1L1-PDGFRα-induced myeloproliferative disease.","method":"Murine bone marrow transplantation model, in vitro proliferation assay with Ba/F3 cells transformed by FIP1L1-PDGFRα","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo murine model plus in vitro kinase inhibition, T674I resistance mechanism confirmed, replicated by subsequent work","pmids":["12781364"],"is_preprint":false},{"year":2004,"finding":"Human Fip1 (hFip1, encoded by FIP1L1) is an integral subunit of CPSF. It interacts with poly(A) polymerase (PAP) and contains an arginine-rich RNA-binding motif that preferentially binds U-rich sequence elements on pre-mRNA. Recombinant hFip1 is sufficient to stimulate in vitro polyadenylation activity of PAP in a U-rich element-dependent manner. hFip1, CPSF160, and PAP form a ternary complex in vitro.","method":"Co-immunoprecipitation, in vitro polyadenylation assay with recombinant proteins, RNA-binding assay, ternary complex reconstitution","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro polyadenylation, direct binding demonstrated, multiple orthogonal methods in single rigorous study","pmids":["14749727"],"is_preprint":false},{"year":2006,"finding":"Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane (JM) domain of PDGFRα, not FIP1L1 itself. The FIP1L1 portion is completely dispensable for kinase activation in vitro and in vivo; truncation of PDGFRα between two conserved tryptophan residues in the JM domain is required for constitutive kinase activation and transforming potential. A complete JM domain is autoinhibitory, but this autoinhibition can be overcome by enforced homodimerization.","method":"Deletion mutagenesis, cell transformation assay, in vitro kinase assay, murine bone marrow transplantation","journal":"Proceedings of the National Academy of Sciences of the USA","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-function mutagenesis combined with in vitro and in vivo models, mechanistic conclusion clearly supported by multiple experimental approaches","pmids":["16690743"],"is_preprint":false},{"year":1995,"finding":"Yeast Fip1 (the ortholog of FIP1L1) directly interacts with poly(A) polymerase (Pap1) in a 1:1 complex. Fip1 is required for polyadenylation but not cleavage of pre-mRNA in vitro. Fip1 also directly interacts with RNA14, a subunit of cleavage factor I (CF I), through co-immunoprecipitation, thereby tethering Pap1 to CF I to confer substrate specificity.","method":"Two-hybrid assay, in vitro reconstitution of 1:1 complex, temperature-sensitive mutant analysis, in vitro 3'-end processing assay, co-immunoprecipitation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined 1:1 stoichiometry, genetic validation via ts-allele, co-IP for RNA14 interaction, foundational mechanistic study","pmids":["7736590"],"is_preprint":false},{"year":2001,"finding":"Yeast Fip1 regulates poly(A) polymerase (Pap1) activity through multiple domains: residues 80–105 bind Pap1 and inhibit its activity by limiting RNA substrate access to Pap1's C-terminal RNA-binding domain (C-RBD); residues 206–220 interact with Yth1 (a CPSF subunit) and are required for specific polyadenylation; residues 105–206 help restrict RNA binding at the C-RBD of Pap1. The C-terminus of Fip1 relieves Fip1-mediated repression of Pap1.","method":"Domain deletion mutagenesis, in vitro binding assays, in vitro polyadenylation assay, yeast viability assay","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with multiple functional domains identified, in vitro mechanistic assays, viability confirming physiological relevance","pmids":["11238938"],"is_preprint":false},{"year":2006,"finding":"Sorafenib is a potent inhibitor of FIP1L1-PDGFRα (wild-type) and the imatinib-resistant FIP1L1-PDGFRα T674I mutant. It inhibits proliferation of transformed Ba/F3 cells and induces apoptosis of EOL-1 cells at nanomolar concentrations, confirmed by Western blot showing direct inhibition of FIP1L1-PDGFRα phosphorylation.","method":"In vitro proliferation assay (Ba/F3 cells), apoptosis assay (EOL-1), Western blot for phospho-PDGFRα","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct kinase inhibition shown by Western blot, cellular functional assays, replicated by subsequent clinical reports","pmids":["16645167"],"is_preprint":false},{"year":2007,"finding":"FIP1L1-PDGFRα induces myeloproliferation in human CD34+ hematopoietic progenitors via activation of PI3K, ERK1/2, and STAT5 signaling pathways. Combined inhibition of PI3K and ERK1/2 significantly reversed FIP1L1-PDGFRα-induced colony formation. Dominant-negative STAT5 partially inhibited colony formation. FIP1L1 residues 30–233 contribute to STAT5 and Akt activation (but not p38/ERK1/2).","method":"Retroviral transduction of human CD34+ progenitors, cytokine-independent colony assay, dominant-negative STAT5 expression, pharmacological inhibitors of PI3K and ERK1/2, Western blot signaling analysis","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative, pharmacological inhibitors, deletion mutants) in primary human progenitor cells","pmids":["17440089"],"is_preprint":false},{"year":2008,"finding":"Crystal structure of yeast poly(A) polymerase (Pap1) in complex with a peptide of Fip1 residues 80–105 at 2.6 Å resolution. The Fip1 peptide binds the outer surface of the C-terminal domain of Pap1. A Pap1 mutant (V498Y, C485R) designed from the structure cannot bind Fip1 but retains full polymerase activity and is lethal in yeast. Fip1 is largely disordered in the absence of Pap1.","method":"X-ray crystallography (2.6 Å), site-directed mutagenesis, yeast viability assay, analytical ultracentrifugation, circular dichroism, limited proteolysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis and functional validation, multiple orthogonal biophysical methods confirming Fip1 disorder","pmids":["18537269"],"is_preprint":false},{"year":2009,"finding":"FIP1L1-PDGFRα and TEL-PDGFRβ fusion proteins escape ubiquitination and proteasomal degradation unlike their wild-type counterparts. Ubiquitination of FIP1L1-PDGFRα is markedly reduced despite Cbl phosphorylation. Protein stability of the fusion is critical for efficient stimulation of cell proliferation and STAT5 activation, demonstrated by an inducible destabilizing domain fusion experiment.","method":"Western blot for ubiquitination and protein levels in Ba/F3 cells and patient leukocytes, destabilizing domain (DD) fusion approach, STAT5 phosphorylation assay","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (ubiquitination, DD fusion, patient material) in single lab","pmids":["19644140"],"is_preprint":false},{"year":2009,"finding":"FIP1L1-PDGFRα confers eosinophil lineage commitment on hematopoietic stem/progenitor cells by activating MEK1/2 and p38 MAPK more intensely than TEL-PDGFRβ. FIP1L1-PDGFRα augments expression of C/EBPα, GATA-1, and GATA-2 while suppressing PU.1 activity via Ras signaling. shRNA knockdown of C/EBPα, GATA-2, and dominant-negative GATA inhibited FIP1L1-PDGFRα-induced eosinophil development.","method":"Retroviral transduction of murine hematopoietic progenitor subsets, cytokine-independent replating assay, bone marrow transplantation, pharmacological MEK/p38 inhibition, shRNA knockdown, luciferase reporter for PU.1 activity, RT-PCR for transcription factor expression","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic knockdown, pharmacological inhibition, luciferase reporter) across defined progenitor subsets with clear mechanistic pathway placement","pmids":["19147501"],"is_preprint":false},{"year":2009,"finding":"FIP1L1-PDGFRα D842V mutation is pan-resistant to sorafenib, imatinib, dasatinib, and PKC412 in vitro. This mutant emerged clinically under sorafenib therapy for T674I-mutant disease, and was identified as a major sorafenib-resistant mutant by ENU mutagenesis screen.","method":"ENU-mutagenesis screen, in vitro proliferation assays with Ba/F3 cells expressing D842V mutant, clinical case report with molecular confirmation","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ENU screen plus in vitro validation; single lab but multiple experimental approaches","pmids":["19212337"],"is_preprint":false},{"year":2005,"finding":"hFip1 (FIP1L1 protein) interacts specifically with the U-rich upstream element of the HPV-16 early polyadenylation signal and enhances polyadenylation at that site.","method":"RNA pulldown/interaction assay (in vitro binding), polyadenylation signal analysis, deletion mapping","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding demonstrated but limited to a single pulldown approach; consistent with established U-rich binding function from EMBO J 2004","pmids":["15767428"],"is_preprint":false},{"year":2011,"finding":"Yeast Fip1 contains a flexible linker region (middle of the protein) required for efficient mRNA polyadenylation. Removal or replacement of the linker reduces polyadenylation efficiency. The linker provides a platform for interactions with other polyadenylation machinery components. A fusion protein of Pap1 directly tethered to Fip1 is fully functional, and direct tethering of Pap1 to RNA increases the rate of poly(A) addition.","method":"In vitro polyadenylation assay, yeast viability assay, deletion/replacement mutagenesis, Pap1-Fip1 fusion protein functional test","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro polyadenylation reconstitution with defined deletion mutants plus yeast in vivo complementation, multiple orthogonal approaches","pmids":["21282348"],"is_preprint":false},{"year":2014,"finding":"Fip1 is essential for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Fip1 promotes stem cell maintenance by activating ESC-specific alternative polyadenylation (APA) profiles through Fip1-RNA interactions and APA site distance. Loss of Fip1 disrupts expression of critical self-renewal factors.","method":"Genetic knockout/knockdown in mouse ESCs, RNA-seq/PAC-seq for APA profiling, somatic reprogramming assay, self-renewal colony assay","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific phenotypic readout (self-renewal failure), genome-wide APA mapping, rescue experiments, multiple orthogonal methods","pmids":["24596251"],"is_preprint":false},{"year":2012,"finding":"FIP1L1-PDGFRα activates JAK2, and JAK2 is required for FIP1L1-PDGFRα-driven cellular proliferation and migration. JAK2 inhibition (siRNA or AG490) in EOL-1 and primary FIP1L1-PDGFRα+ CEL cells reduces proliferation, induces apoptosis, and blocks IL-5-induced migration. JAK2 mediates STAT3 (but not STAT5) activation and also activates PI3K/Akt and NF-κB downstream.","method":"siRNA knockdown of JAK2, pharmacological inhibition (AG490), Western blot for signaling, proliferation and apoptosis assays, migration assay, patient primary cells","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological approaches in cell lines and patient primary cells, but single lab","pmids":["22523564"],"is_preprint":false},{"year":2012,"finding":"FIP1L1-PDGFRα activates NF-κB via PI3K. NF-κB is required for FIP1L1-PDGFRα-driven eosinophil differentiation from human CD34+ progenitors, including expression of IL-5Rα and eosinophil peroxidase. Bortezomib and the IκB kinase inhibitor BMS-345541 block proliferation of EOL-1 cells.","method":"Lentiviral transduction of human CD34+ progenitors, PI3K inhibitor, dominant-negative IκB expression, pharmacological NF-κB inhibition, gene expression microarray","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative and pharmacological approaches in human primary cells; single lab, multiple complementary methods","pmids":["22271894"],"is_preprint":false},{"year":2014,"finding":"SHP2 tyrosine phosphatase binds directly to tyrosine 720 of FIP1L1-PDGFRα and is required for ERK signaling and cell transformation. Mutation of Y720 or SHP2 knockdown reduces proliferation and ERK (but not STAT5) signaling in Ba/F3 cells and in human CD34+ progenitors. SHP2 is not required for wild-type PDGFR-driven ERK activation, indicating an oncogene-specific shift in SHP2 function.","method":"Site-directed mutagenesis (12 tyrosine residues), SHP2 siRNA knockdown, in vivo murine myeloproliferation assay, human CD34+ progenitor assay, co-immunoprecipitation (SHP2 binding to Y720)","journal":"Molecular Oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct co-IP of SHP2 binding to Y720, mutagenesis, siRNA knockdown in multiple cell systems including primary human progenitors, and in vivo validation","pmids":["24618081"],"is_preprint":false},{"year":2014,"finding":"In FIP1L1-RARA fusion, the FIP1 motif of FIP1L1 is required for homodimerization and transcriptional repressor activity. In FIP1L1-PDGFRα, the C-terminal PDGFRα portion can form homodimers independently, making FIP1L1 dispensable for constitutive kinase activation, but FIP1L1 contributes to complete IL-3 independence of transformed cells.","method":"Deletion mutant analysis, hematopoietic cell transformation assay (BAF-B03), cytokine independence assay","journal":"Annals of Hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutant series with functional readout in cell lines; single lab, no structural confirmation","pmids":["24763514"],"is_preprint":false},{"year":2015,"finding":"The F604S mutation in FIP1L1-PDGFRα stabilizes the fusion protein by creating a binding site for the SHP-2 phosphatase domain, reducing autophosphorylation and consequently reducing SRC activation. SRC normally promotes FIP1L1-PDGFRα degradation via CBL ubiquitination; reduced SRC activation thus prolongs protein half-life. SRC inhibition or knockdown phenocopies the protein stabilization seen with F604S.","method":"Pulse-chase protein stability assay, site-directed mutagenesis, co-immunoprecipitation (SHP-2 binding), SRC inhibition and knockdown, Western blot for autophosphorylation and CBL","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct co-IP demonstrating SHP-2 binding, pulse-chase for stability, SRC siRNA and inhibitor confirming mechanism, multiple orthogonal methods in single lab","pmids":["25761934"],"is_preprint":false},{"year":2020,"finding":"Human CPSF30 ZF4-ZF5 binds hFip1 with 1:2 stoichiometry (one hFip1 molecule per zinc finger, ZF4 and ZF5). Crystal structure at 1.9 Å reveals a conserved binding mode for each ZF. ZF4 has higher affinity for hFip1 (Kd = 1.8 nM). Two copies of the catalytic module of PAP are recruited by the CPSF30-hFip1 complex in vitro, and both hFip1 binding sites in CPSF30 can support polyadenylation.","method":"X-ray crystallography (1.9 Å), fluorescence polarization binding assay, mutagenesis, in vitro polyadenylation assay","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus quantitative binding assay plus in vitro functional polyadenylation assay, multiple orthogonal methods in single rigorous study","pmids":["33122294"],"is_preprint":false},{"year":2021,"finding":"Yeast Fip1, within the reconstituted ~850 kDa CPF complex, anchors poly(A) polymerase Pap1 via an interaction with zinc finger 4 of Yth1. The intrinsically disordered region (IDR) of Fip1 connecting the Yth1- and Pap1-binding sites remains highly dynamic within CPF, as demonstrated by NMR spectroscopy on selectively labeled Fip1 incorporated into the recombinant complex.","method":"Fully recombinant CPF reconstitution, NMR spectroscopy (selective isotope labeling), genetic interaction (Fip1-Yth1 ZF4 interaction mapped)","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of recombinant megadalton complex, NMR characterization of dynamics, multiple orthogonal methods in single rigorous study","pmids":["34593603"],"is_preprint":false},{"year":2022,"finding":"CPSF contains two copies of hFip1, each binding to ZF4 and ZF5 of CPSF30 (crystal structures reported). The two hFip1 copies are functionally redundant in recruiting one copy of PAP, increasing processivity of RNA polyadenylation. hFip1 interacts with CstF77 via a short motif in its N-terminal 'acidic' region; CstF77 competitively inhibits CPSF-dependent PAP recruitment and polyadenylation.","method":"X-ray crystallography (hFip1-CPSF30 and hFip1-CstF77 complexes), in vitro polyadenylation assay, mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — two crystal structures plus in vitro polyadenylation functional assays plus mutagenesis, multiple orthogonal methods validating structural findings","pmids":["36073787"],"is_preprint":false},{"year":2021,"finding":"FIP1L1 (hFip1) promotes 3'UTR shortening of NLRP3 mRNA via its arginine-rich domain binding to the proximal poly(A) site (pPAS) of NLRP3 mRNA, thereby upregulating NLRP3 expression and amplifying inflammation in kidney injury. FIP1L1 is upregulated by oxidative stress and is required for oxidative stress-induced NLRP3 upregulation.","method":"siRNA knockdown (in vitro and in vivo UUO/IRI models), RNA-IP (FIP1L1 binding to NLRP3 pPAS), 3'RACE/APA profiling, Western blot, inflammation/fibrosis functional assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP for direct binding plus functional KD in vivo; single lab, two orthogonal methods","pmids":["34011928"],"is_preprint":false},{"year":2006,"finding":"Yeast Fip1 is phosphorylated in vitro by protein kinase CK2 (but not CK1) at serine residues 73 and 77, as identified by MALDI-MS. CK2α' and holoenzyme phosphorylate Fip1 with Km of ~1.3–1.4 µM.","method":"In vitro kinase assay with recombinant CK2, MALDI-MS identification of phosphorylation sites","journal":"Molecular and Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro phosphorylation assay with site identification by MS, but functional consequence not established and single lab","pmids":["16496213"],"is_preprint":false},{"year":2007,"finding":"FIP1L1-PDGFRα induces proliferation of EOL-1 eosinophilic leukemia cells through upregulation of c-Myc via ERK and JNK signaling pathways. Imatinib inhibits proliferation and decreases c-Myc, phospho-ERK, and phospho-JNK. MEK inhibitor (U0126) and JNK inhibitor (SP600125) also reduce c-Myc expression and proliferation. FIP1L1-PDGFRα is not required for inhibition of eosinophil differentiation.","method":"Western blot, pharmacological inhibitors (imatinib, U0126, SP600125), RT-PCR for c-Myc in EOL-1 cells","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitors with multiple signaling readouts; single lab without genetic validation of the pathway","pmids":["18086564"],"is_preprint":false},{"year":2013,"finding":"FIP1L1-PDGFRα (F/P) upregulates oncostatin M (OSM) expression in a STAT5-dependent manner. OSM secreted by neoplastic eosinophils stimulates stromal cell proliferation and upregulates SDF-1/CXCL12 production in fibroblasts, which in turn induces migration of EOL-1 cells—constituting a paracrine loop contributing to tissue fibrosis and eosinophil accumulation.","method":"Lentiviral F/P transduction of cell lines, doxycycline-inducible F/P in Ba/F3, STAT5 inhibition, immunohistochemistry of patient material, gene expression analysis, proliferation and chemotaxis assays","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system plus patient tissue validation plus functional migration assay; single lab","pmids":["23621172"],"is_preprint":false}],"current_model":"FIP1L1 encodes two functionally distinct proteins: (1) as the canonical mRNA 3'-end processing factor hFip1, it is an intrinsically disordered, multivalent scaffold subunit of CPSF that directly binds PAP (recruiting it to the cleavage/polyadenylation complex via CPSF30 ZF4/ZF5), stimulates PAP activity in a U-rich element-dependent manner, interacts with CstF77 to competitively regulate PAP recruitment, and controls alternative polyadenylation to regulate gene expression in stem cell self-renewal and disease contexts; (2) as the N-terminal fusion partner in FIP1L1-PDGFRα (generated by cryptic del(4)(q12)), FIP1L1 itself is dispensable for kinase activation—constitutive activity arises from disruption of the PDGFRα juxtamembrane autoinhibitory domain—but the fusion escapes ubiquitination/degradation, signals through PI3K/ERK/STAT5/JAK2/NF-κB to drive eosinophil lineage commitment via C/EBPα, GATA-2, and Ras/MEK cascades, and is inhibited by imatinib with resistance conferred by T674I, D842V, S601P, or F604S mutations in the kinase domain."},"narrative":{"mechanistic_narrative":"FIP1L1 encodes hFip1, an intrinsically disordered, multivalent scaffold subunit of the cleavage and polyadenylation specificity factor (CPSF) that couples poly(A) polymerase (PAP) to pre-mRNA 3'-end processing [PMID:14749727, PMID:7736590]. hFip1 directly binds PAP and an arginine-rich motif preferentially recognizes U-rich pre-mRNA elements, and recombinant hFip1 is sufficient to stimulate PAP polyadenylation activity in a U-rich-element-dependent manner [PMID:14749727]. Within CPSF, two copies of hFip1 are tethered through the ZF4 and ZF5 zinc fingers of CPSF30, and these copies act redundantly to recruit PAP and increase polyadenylation processivity, while an N-terminal acidic motif of hFip1 binds CstF77 to competitively modulate PAP recruitment [PMID:33122294, PMID:36073787]. The disordered linker connecting the CPSF-anchoring and PAP-binding sites remains highly dynamic within the assembled complex, consistent with a flexible-tether mechanism that positions PAP near RNA [PMID:21282348, PMID:34593603]. Through control of alternative polyadenylation, hFip1 is essential for embryonic stem cell self-renewal and somatic reprogramming [PMID:24596251] and drives 3'UTR shortening of NLRP3 mRNA to amplify inflammation under oxidative stress [PMID:34011928]. Independently, FIP1L1 is the N-terminal partner of the FIP1L1-PDGFRα fusion generated by a chromosome 4q12 deletion, a constitutively active tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib, with the T674I and D842V kinase-domain mutations conferring resistance [PMID:12660384, PMID:19212337]; this fusion underlies a myeloproliferative/chronic eosinophilic leukemia phenotype. Constitutive activation arises from disruption of the PDGFRα juxtamembrane autoinhibitory domain rather than from FIP1L1 itself, which is dispensable for kinase activation [PMID:16690743]. The fusion escapes ubiquitination and proteasomal degradation, and signals through PI3K/ERK/STAT5, JAK2, SHP2, and NF-κB to drive eosinophil lineage commitment via C/EBPα and GATA-2 [PMID:17440089, PMID:19644140, PMID:19147501, PMID:24618081].","teleology":[{"year":1995,"claim":"Established the founding mechanism: Fip1 physically links poly(A) polymerase to the 3'-end processing machinery, answering how PAP is recruited and made substrate-specific.","evidence":"Two-hybrid, in vitro reconstitution of a 1:1 Fip1-Pap1 complex, ts-mutant and 3'-processing assays in yeast","pmids":["7736590"],"confidence":"High","gaps":["Structural basis of the Fip1-Pap1 interface not defined","Human ortholog function not yet shown"]},{"year":2001,"claim":"Dissected Fip1 into discrete functional domains, showing it both inhibits and directs PAP activity through separable Pap1-binding, Yth1-binding, and RNA-restricting regions.","evidence":"Domain deletion mutagenesis, in vitro polyadenylation, and yeast viability assays","pmids":["11238938"],"confidence":"High","gaps":["Mechanism by which the C-terminus relieves repression not structurally resolved","In vivo relevance of individual domains in mammals untested"]},{"year":2003,"claim":"Revealed an entirely distinct disease-driving role: a 4q12 deletion fuses FIP1L1 to PDGFRA to create a constitutively active, imatinib-sensitive kinase, defining the molecular basis of a myeloproliferative disease.","evidence":"Chromosomal analysis, RT-PCR, Ba/F3 transformation, in vitro kinase inhibition; plus murine BMT model with PKC412","pmids":["12660384","12781364"],"confidence":"High","gaps":["Contribution of the FIP1L1 portion to activation not yet resolved","Resistance mechanisms beyond T674I unknown"]},{"year":2004,"claim":"Identified human hFip1 as an integral CPSF subunit that binds PAP and U-rich RNA and stimulates polyadenylation, establishing functional conservation of the yeast mechanism in humans.","evidence":"Co-IP, recombinant in vitro polyadenylation, RNA-binding and ternary complex reconstitution","pmids":["14749727"],"confidence":"High","gaps":["Stoichiometry within CPSF not determined","Genome-wide targets and APA roles unaddressed"]},{"year":2006,"claim":"Resolved that FIP1L1-PDGFRα activation derives from loss of the PDGFRα juxtamembrane autoinhibition, not from FIP1L1, clarifying the oncogenic mechanism.","evidence":"Deletion mutagenesis, in vitro kinase assay, cell transformation, murine BMT","pmids":["16690743"],"confidence":"High","gaps":["Why the fusion is favored over other JM-disrupting events not addressed","Role of FIP1L1 sequences in fine-tuning signaling left open"]},{"year":2006,"claim":"Identified CK2 as a kinase phosphorylating yeast Fip1, raising the possibility of post-translational regulation of polyadenylation.","evidence":"In vitro CK2 kinase assay with MALDI-MS site identification","pmids":["16496213"],"confidence":"Medium","gaps":["Functional consequence of S73/S77 phosphorylation not established","Phosphorylation not demonstrated in vivo"]},{"year":2007,"claim":"Mapped the proliferative signaling output of FIP1L1-PDGFRα to PI3K, ERK1/2, and STAT5 in primary human progenitors, defining therapeutically relevant nodes.","evidence":"CD34+ retroviral transduction, dominant-negative STAT5, PI3K/ERK inhibitors, colony assays; c-Myc via ERK/JNK in EOL-1","pmids":["17440089","18086564"],"confidence":"High","gaps":["Relative contribution of each pathway to in vivo disease unclear","Connection between signaling and lineage choice not yet made"]},{"year":2008,"claim":"Provided the structural basis of Fip1-PAP recognition and confirmed Fip1 is intrinsically disordered absent its partner.","evidence":"X-ray crystallography of Pap1-Fip1(80-105), structure-guided mutagenesis, yeast viability, CD and ultracentrifugation","pmids":["18537269"],"confidence":"High","gaps":["Conformation of full-length Fip1 within CPSF not resolved","Human complex architecture not addressed"]},{"year":2009,"claim":"Explained why FIP1L1-PDGFRα accumulates: it escapes ubiquitin-mediated degradation, and its protein stability is required for proliferation and STAT5 activation.","evidence":"Ubiquitination Western blots, destabilizing-domain fusion, patient leukocytes","pmids":["19644140"],"confidence":"Medium","gaps":["Molecular reason for reduced ubiquitination despite Cbl phosphorylation unresolved","Single-lab finding"]},{"year":2009,"claim":"Connected fusion signaling to cell fate, showing FIP1L1-PDGFRα enforces eosinophil lineage commitment via MEK/p38, C/EBPα and GATA-2 induction, and PU.1 suppression.","evidence":"Murine progenitor transduction, BMT, MEK/p38 inhibitors, shRNA, PU.1 luciferase reporter; plus D842V pan-resistance ENU screen","pmids":["19147501","19212337"],"confidence":"High","gaps":["Direct transcriptional targets of induced factors not mapped","Why eosinophil-specific among myeloid fates incompletely defined"]},{"year":2012,"claim":"Extended the signaling network to JAK2 and PI3K-dependent NF-κB as required effectors of proliferation, migration, and eosinophil differentiation.","evidence":"JAK2 siRNA/AG490 and dominant-negative IκB/NF-κB inhibition in EOL-1, primary CEL cells, and CD34+ progenitors","pmids":["22523564","22271894"],"confidence":"Medium","gaps":["Hierarchy among JAK2, PI3K, NF-κB nodes not fully ordered","Single-lab studies"]},{"year":2014,"claim":"Defined an oncogene-specific role for SHP2 binding to phosphotyrosine 720 of the fusion in driving ERK signaling and transformation.","evidence":"Tyrosine mutagenesis, SHP2 co-IP and siRNA, Ba/F3, CD34+ progenitors, murine model","pmids":["24618081"],"confidence":"High","gaps":["Why SHP2 dependence is fusion-specific versus wild-type PDGFR not mechanistically explained"]},{"year":2014,"claim":"Established hFip1 as essential for stem cell identity by controlling ESC-specific alternative polyadenylation, linking the polyadenylation scaffold to cell-fate gene expression.","evidence":"Mouse ESC knockout/knockdown, PAC-seq/RNA-seq APA profiling, reprogramming and self-renewal assays; FIP1 motif homodimerization in fusion contexts","pmids":["24596251","24763514"],"confidence":"High","gaps":["Which APA target transcripts drive self-renewal not fully resolved","How Fip1-RNA interactions set APA site choice mechanistically unclear"]},{"year":2015,"claim":"Resolved a drug-resistance mechanism in which the F604S mutation stabilizes the fusion by recruiting SHP-2 to dampen autophosphorylation and SRC-driven CBL ubiquitination.","evidence":"Pulse-chase stability, mutagenesis, SHP-2 co-IP, SRC inhibition/knockdown","pmids":["25761934"],"confidence":"High","gaps":["Generality of SRC-CBL turnover control across resistance mutants untested"]},{"year":2022,"claim":"Delivered the structural and functional architecture of the human CPSF-hFip1 module: two redundant hFip1 copies on CPSF30 ZF4/ZF5 recruit PAP for processivity, and an hFip1 acidic motif binds CstF77 to competitively regulate PAP recruitment.","evidence":"X-ray crystallography of hFip1-CPSF30 and hFip1-CstF77, fluorescence polarization, in vitro polyadenylation, mutagenesis; recombinant CPF NMR showing IDR dynamics; yeast linker analysis","pmids":["33122294","36073787","34593603","21282348"],"confidence":"High","gaps":["How CstF77 competition is regulated during processing in cells unclear","Whether the two hFip1 sites are differentially used on specific transcripts unknown"]},{"year":2021,"claim":"Demonstrated a disease-relevant APA function for hFip1 in inflammation, shortening NLRP3 3'UTR to upregulate NLRP3 under oxidative stress.","evidence":"siRNA in vitro/in vivo kidney injury models, RNA-IP at NLRP3 proximal poly(A) site, 3'RACE/APA profiling; plus STAT5-dependent OSM/CXCL12 paracrine loop in fusion disease","pmids":["34011928","23621172"],"confidence":"Medium","gaps":["Breadth of inflammation-relevant APA targets beyond NLRP3 unknown","Single-lab findings"]},{"year":null,"claim":"How the two functionally distinct activities of FIP1L1 — the CPSF polyadenylation scaffold and the oncogenic fusion N-terminus — are regulated in physiological versus disease contexts, including the in vivo determinants of APA target selection and the full set of post-translational controls, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No comprehensive map of hFip1-controlled APA targets in normal tissues","Functional role of CK2 phosphorylation undefined","Mechanism integrating signaling, stability, and lineage output in fusion disease incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,12,23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,20,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5,22]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,14,23]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,14,20,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,4,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,17,16]}],"complexes":["CPSF","CPF (yeast cleavage and polyadenylation factor)"],"partners":["PAP/PAP1","CPSF30","CSTF77","CPSF160","YTH1","RNA14","PDGFRA","SHP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UN15","full_name":"Pre-mRNA 3'-end-processing factor FIP1","aliases":["FIP1-like 1 protein","Factor interacting with PAP","Rearranged in hypereosinophilia"],"length_aa":594,"mass_kda":66.5,"function":"Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. FIP1L1 contributes to poly(A) site recognition and stimulates poly(A) addition. Binds to U-rich RNA sequence elements surrounding the poly(A) site. May act to tether poly(A) polymerase to the CPSF complex","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6UN15/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/FIP1L1","classification":"Common Essential","n_dependent_lines":1141,"n_total_lines":1208,"dependency_fraction":0.9445364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FIP1L1","total_profiled":1310},"omim":[{"mim_id":"612839","title":"TET METHYLCYTOSINE DIOXYGENASE 2; TET2","url":"https://www.omim.org/entry/612839"},{"mim_id":"607686","title":"FIP1-LIKE 1; FIP1L1","url":"https://www.omim.org/entry/607686"},{"mim_id":"607685","title":"HYPEREOSINOPHILIC SYNDROME, IDIOPATHIC; HES","url":"https://www.omim.org/entry/607685"},{"mim_id":"602388","title":"SYMPLEKIN; SYMPK","url":"https://www.omim.org/entry/602388"},{"mim_id":"173490","title":"PLATELET-DERIVED GROWTH FACTOR RECEPTOR, ALPHA; PDGFRA","url":"https://www.omim.org/entry/173490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FIP1L1"},"hgnc":{"alias_symbol":["DKFZp586K0717","FIP1","hFip1"],"prev_symbol":[]},"alphafold":{"accession":"Q6UN15","domains":[{"cath_id":"1.10.287","chopping":"148-197","consensus_level":"medium","plddt":79.5044,"start":148,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UN15","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UN15-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UN15-F1-predicted_aligned_error_v6.png","plddt_mean":55.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FIP1L1","jax_strain_url":"https://www.jax.org/strain/search?query=FIP1L1"},"sequence":{"accession":"Q6UN15","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UN15.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UN15/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UN15"}},"corpus_meta":[{"pmid":"12660384","id":"PMC_12660384","title":"A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.","date":"2003","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12660384","citation_count":1314,"is_preprint":false},{"pmid":"12842979","id":"PMC_12842979","title":"CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12842979","citation_count":298,"is_preprint":false},{"pmid":"15284118","id":"PMC_15284118","title":"FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15284118","citation_count":247,"is_preprint":false},{"pmid":"15070659","id":"PMC_15070659","title":"The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15070659","citation_count":213,"is_preprint":false},{"pmid":"14749727","id":"PMC_14749727","title":"Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/14749727","citation_count":209,"is_preprint":false},{"pmid":"19262599","id":"PMC_19262599","title":"Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates.","date":"2009","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/19262599","citation_count":203,"is_preprint":false},{"pmid":"12781364","id":"PMC_12781364","title":"PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.","date":"2003","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/12781364","citation_count":187,"is_preprint":false},{"pmid":"17299092","id":"PMC_17299092","title":"Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17299092","citation_count":159,"is_preprint":false},{"pmid":"17666373","id":"PMC_17666373","title":"The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study.","date":"2007","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/17666373","citation_count":156,"is_preprint":false},{"pmid":"24596251","id":"PMC_24596251","title":"Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/24596251","citation_count":139,"is_preprint":false},{"pmid":"14973504","id":"PMC_14973504","title":"Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias.","date":"2004","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/14973504","citation_count":133,"is_preprint":false},{"pmid":"17377585","id":"PMC_17377585","title":"Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma.","date":"2007","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/17377585","citation_count":126,"is_preprint":false},{"pmid":"7736590","id":"PMC_7736590","title":"The FIP1 gene encodes a component of a yeast pre-mRNA polyadenylation factor that directly interacts with poly(A) polymerase.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7736590","citation_count":123,"is_preprint":false},{"pmid":"18843283","id":"PMC_18843283","title":"Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias.","date":"2008","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/18843283","citation_count":122,"is_preprint":false},{"pmid":"16645167","id":"PMC_16645167","title":"Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16645167","citation_count":119,"is_preprint":false},{"pmid":"16406016","id":"PMC_16406016","title":"FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature.","date":"2006","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/16406016","citation_count":107,"is_preprint":false},{"pmid":"16690743","id":"PMC_16690743","title":"Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16690743","citation_count":101,"is_preprint":false},{"pmid":"16030188","id":"PMC_16030188","title":"The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16030188","citation_count":99,"is_preprint":false},{"pmid":"19212337","id":"PMC_19212337","title":"FIP1L1-PDGFRalpha D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRalpha T674I eosinophilic leukemia with single agent sorafenib.","date":"2009","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/19212337","citation_count":99,"is_preprint":false},{"pmid":"14630792","id":"PMC_14630792","title":"The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/14630792","citation_count":85,"is_preprint":false},{"pmid":"17628645","id":"PMC_17628645","title":"KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities.","date":"2007","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17628645","citation_count":81,"is_preprint":false},{"pmid":"18307562","id":"PMC_18307562","title":"A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients.","date":"2008","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/18307562","citation_count":67,"is_preprint":false},{"pmid":"15767428","id":"PMC_15767428","title":"A 57-nucleotide upstream early polyadenylation element in human papillomavirus type 16 interacts with hFip1, CstF-64, hnRNP C1/C2, and polypyrimidine tract binding protein.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15767428","citation_count":62,"is_preprint":false},{"pmid":"17440089","id":"PMC_17440089","title":"Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17440089","citation_count":62,"is_preprint":false},{"pmid":"16418325","id":"PMC_16418325","title":"The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16418325","citation_count":62,"is_preprint":false},{"pmid":"16409293","id":"PMC_16409293","title":"Multilineage involvement of the fusion gene in patients with FIP1L1/PDGFRA-positive hypereosinophilic syndrome.","date":"2006","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/16409293","citation_count":60,"is_preprint":false},{"pmid":"14676627","id":"PMC_14676627","title":"The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia.","date":"2004","source":"Current opinion in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/14676627","citation_count":57,"is_preprint":false},{"pmid":"11238938","id":"PMC_11238938","title":"Fip1 regulates the activity of Poly(A) polymerase through multiple interactions.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11238938","citation_count":57,"is_preprint":false},{"pmid":"32720700","id":"PMC_32720700","title":"Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.","date":"2020","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/32720700","citation_count":57,"is_preprint":false},{"pmid":"15921374","id":"PMC_15921374","title":"The hypereosinophilic syndrome: fluorescence in situ hybridization detects the del(4)(q12)-FIP1L1/PDGFRA but not genomic rearrangements of other tyrosine kinases.","date":"2005","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/15921374","citation_count":51,"is_preprint":false},{"pmid":"22447844","id":"PMC_22447844","title":"Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor α and bcr-abl oncogene addiction in malignant hematologic cells.","date":"2012","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/22447844","citation_count":48,"is_preprint":false},{"pmid":"22271894","id":"PMC_22271894","title":"ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-κB.","date":"2012","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/22271894","citation_count":44,"is_preprint":false},{"pmid":"19644140","id":"PMC_19644140","title":"The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation.","date":"2009","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/19644140","citation_count":43,"is_preprint":false},{"pmid":"15257945","id":"PMC_15257945","title":"FIP1L1-PDGFRA and c-kit D816V mutation-based clonality studies in systemic mast cell disease associated with eosinophilia.","date":"2004","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/15257945","citation_count":41,"is_preprint":false},{"pmid":"19144405","id":"PMC_19144405","title":"Success of short-term, higher-dose imatinib mesylate to induce clinical response in FIP1L1-PDGFRalpha-negative hypereosinophilic syndrome.","date":"2009","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/19144405","citation_count":40,"is_preprint":false},{"pmid":"31111599","id":"PMC_31111599","title":"The polyadenylation factor FIP1 is important for plant development and root responses to abiotic stresses.","date":"2019","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31111599","citation_count":38,"is_preprint":false},{"pmid":"20610657","id":"PMC_20610657","title":"FIP1/RCP binding to Golgin-97 regulates retrograde transport from recycling endosomes to the trans-Golgi network.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20610657","citation_count":38,"is_preprint":false},{"pmid":"34047477","id":"PMC_34047477","title":"Glioma glycolipid metabolism: MSI2-SNORD12B-FIP1L1-ZBTB4 feedback loop as a potential treatment target.","date":"2021","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34047477","citation_count":36,"is_preprint":false},{"pmid":"17495975","id":"PMC_17495975","title":"The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1.","date":"2007","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/17495975","citation_count":36,"is_preprint":false},{"pmid":"16682077","id":"PMC_16682077","title":"Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells.","date":"2006","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/16682077","citation_count":35,"is_preprint":false},{"pmid":"18987650","id":"PMC_18987650","title":"Detection and molecular monitoring of FIP1L1-PDGFRA-positive disease by analysis of patient-specific genomic DNA fusion junctions.","date":"2008","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/18987650","citation_count":35,"is_preprint":false},{"pmid":"24407160","id":"PMC_24407160","title":"Identification of Ponatinib as a potent inhibitor of growth, migration, and activation of neoplastic eosinophils carrying FIP1L1-PDGFRA.","date":"2014","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/24407160","citation_count":34,"is_preprint":false},{"pmid":"16344672","id":"PMC_16344672","title":"Idiopathic hypereosinophilic syndrome in children: report of a 7-year-old boy with FIP1L1-PDGFRA rearrangement.","date":"2005","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16344672","citation_count":33,"is_preprint":false},{"pmid":"16920206","id":"PMC_16920206","title":"The Rab11-FIP1/RCP gene codes for multiple protein transcripts related to the plasma membrane recycling system.","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16920206","citation_count":30,"is_preprint":false},{"pmid":"34011928","id":"PMC_34011928","title":"Alternative polyadenylation trans-factor FIP1 exacerbates UUO/IRI-induced kidney injury and contributes to AKI-CKD transition via ROS-NLRP3 axis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34011928","citation_count":29,"is_preprint":false},{"pmid":"16406018","id":"PMC_16406018","title":"Systemic mastocytosis (SM) associated with chronic eosinophilic leukemia (SM-CEL): detection of FIP1L1/PDGFRalpha, classification by WHO criteria, and response to therapy with imatinib.","date":"2006","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/16406018","citation_count":29,"is_preprint":false},{"pmid":"16387954","id":"PMC_16387954","title":"Cough and hypereosinophilia due to FIP1L1-PDGFRA fusion gene with tyrosine kinase activity.","date":"2006","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/16387954","citation_count":28,"is_preprint":false},{"pmid":"18537269","id":"PMC_18537269","title":"Structure of yeast poly(A) polymerase in complex with a peptide from Fip1, an intrinsically disordered protein.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18537269","citation_count":27,"is_preprint":false},{"pmid":"19147501","id":"PMC_19147501","title":"FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19147501","citation_count":27,"is_preprint":false},{"pmid":"22523564","id":"PMC_22523564","title":"Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22523564","citation_count":27,"is_preprint":false},{"pmid":"18987651","id":"PMC_18987651","title":"The molecular anatomy of the FIP1L1-PDGFRA fusion gene.","date":"2008","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/18987651","citation_count":26,"is_preprint":false},{"pmid":"27120808","id":"PMC_27120808","title":"Long-term outcomes of imatinib in patients with FIP1L1/ PDGFRA associated chronic eosinophilic leukemia: experience of a single center in China.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27120808","citation_count":26,"is_preprint":false},{"pmid":"24040321","id":"PMC_24040321","title":"The rab11 effector protein FIP1 regulates adiponectin trafficking and secretion.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24040321","citation_count":25,"is_preprint":false},{"pmid":"18619723","id":"PMC_18619723","title":"Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRalpha.","date":"2008","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/18619723","citation_count":24,"is_preprint":false},{"pmid":"33403789","id":"PMC_33403789","title":"Rab11-FIP1 mediates epithelial-mesenchymal transition and invasion in esophageal cancer.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33403789","citation_count":23,"is_preprint":false},{"pmid":"28223489","id":"PMC_28223489","title":"Structural basis of jasmonate-amido synthetase FIN219 in complex with glutathione S-transferase FIP1 during the JA signal regulation.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28223489","citation_count":21,"is_preprint":false},{"pmid":"17914408","id":"PMC_17914408","title":"The severity of FIP1L1-PDGFRA-positive chronic eosinophilic leukaemia is associated with polymorphic variation at the IL5RA locus.","date":"2007","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/17914408","citation_count":21,"is_preprint":false},{"pmid":"19210352","id":"PMC_19210352","title":"A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome.","date":"2009","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/19210352","citation_count":20,"is_preprint":false},{"pmid":"24472312","id":"PMC_24472312","title":"Ponatinib efficiently kills imatinib-resistant chronic eosinophilic leukemia cells harboring gatekeeper mutant T674I FIP1L1-PDGFRα: roles of Mcl-1 and β-catenin.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24472312","citation_count":20,"is_preprint":false},{"pmid":"24763514","id":"PMC_24763514","title":"FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia.","date":"2014","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/24763514","citation_count":19,"is_preprint":false},{"pmid":"16502585","id":"PMC_16502585","title":"Detection of the FIP1L1-PDGFRA fusion in idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia.","date":"2006","source":"Methods in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16502585","citation_count":19,"is_preprint":false},{"pmid":"21282348","id":"PMC_21282348","title":"A flexible linker region in Fip1 is needed for efficient mRNA polyadenylation.","date":"2011","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21282348","citation_count":17,"is_preprint":false},{"pmid":"19728396","id":"PMC_19728396","title":"Clinical characteristics of patients with chronic eosinophilic leukaemia (CEL) harbouring FIP1L1-PDGFRA fusion transcript--results of Polish multicentre study.","date":"2010","source":"Hematological oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19728396","citation_count":17,"is_preprint":false},{"pmid":"34593603","id":"PMC_34593603","title":"Dynamics in Fip1 regulate eukaryotic mRNA 3' end processing.","date":"2021","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/34593603","citation_count":16,"is_preprint":false},{"pmid":"19671059","id":"PMC_19671059","title":"Triptolide abrogates oncogene FIP1L1-PDGFRalpha addiction and induces apoptosis in hypereosinophilic syndrome.","date":"2009","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/19671059","citation_count":16,"is_preprint":false},{"pmid":"19187542","id":"PMC_19187542","title":"FIP1L1-PDGFRA molecular analysis in the differential diagnosis of eosinophilia.","date":"2009","source":"BMC blood disorders","url":"https://pubmed.ncbi.nlm.nih.gov/19187542","citation_count":16,"is_preprint":false},{"pmid":"24618081","id":"PMC_24618081","title":"The tyrosine phosphatase SHP2 is required for cell transformation by the receptor tyrosine kinase mutants FIP1L1-PDGFRα and PDGFRα D842V.","date":"2014","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24618081","citation_count":16,"is_preprint":false},{"pmid":"34304603","id":"PMC_34304603","title":"FIP1L1-PDGFRA-Associated Hypereosinophilic Syndrome as a Treatable Cause of Watershed Infarction.","date":"2021","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/34304603","citation_count":16,"is_preprint":false},{"pmid":"17215855","id":"PMC_17215855","title":"FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells.","date":"2007","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/17215855","citation_count":15,"is_preprint":false},{"pmid":"18028420","id":"PMC_18028420","title":"Synchronous FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma: a bilineal clonal malignancy.","date":"2007","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/18028420","citation_count":15,"is_preprint":false},{"pmid":"24669761","id":"PMC_24669761","title":"Discovery of imatinib-responsive FIP1L1-PDGFRA mutation during refractory acute myeloid leukemia transformation of chronic myelomonocytic leukemia.","date":"2014","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24669761","citation_count":15,"is_preprint":false},{"pmid":"33122294","id":"PMC_33122294","title":"Molecular mechanism for the interaction between human CPSF30 and hFip1.","date":"2020","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/33122294","citation_count":14,"is_preprint":false},{"pmid":"20523072","id":"PMC_20523072","title":"FIP1L1/PDGFR alpha-associated systemic mastocytosis.","date":"2010","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20523072","citation_count":14,"is_preprint":false},{"pmid":"36073787","id":"PMC_36073787","title":"Fip1 is a multivalent interaction scaffold for processing factors in human mRNA 3' end biogenesis.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36073787","citation_count":13,"is_preprint":false},{"pmid":"18539901","id":"PMC_18539901","title":"FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18539901","citation_count":13,"is_preprint":false},{"pmid":"28396819","id":"PMC_28396819","title":"Rab11-FIP1 phosphorylation by MARK2 regulates polarity in MDCK cells.","date":"2017","source":"Cellular logistics","url":"https://pubmed.ncbi.nlm.nih.gov/28396819","citation_count":12,"is_preprint":false},{"pmid":"25761934","id":"PMC_25761934","title":"F604S exchange in FIP1L1-PDGFRA enhances FIP1L1-PDGFRA protein stability via SHP-2 and SRC: a novel mode of kinase inhibitor resistance.","date":"2015","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/25761934","citation_count":12,"is_preprint":false},{"pmid":"24009732","id":"PMC_24009732","title":"The conformational control inhibitor of tyrosine kinases DCC-2036 is effective for imatinib-resistant cells expressing T674I FIP1L1-PDGFRα.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24009732","citation_count":12,"is_preprint":false},{"pmid":"16513534","id":"PMC_16513534","title":"Chronic eosinophilic leukemia with the FIP1L1-PDGFRalpha fusion gene in a patient with a history of combination chemotherapy.","date":"2006","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/16513534","citation_count":11,"is_preprint":false},{"pmid":"34638806","id":"PMC_34638806","title":"Rab11-FIP1 and Rab11-FIP5 Regulate pIgR/pIgA Transcytosis through TRIM21-Mediated Polyubiquitination.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34638806","citation_count":10,"is_preprint":false},{"pmid":"25431951","id":"PMC_25431951","title":"Antitumor activity of S116836, a novel tyrosine kinase inhibitor, against imatinib-resistant FIP1L1-PDGFRα-expressing cells.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25431951","citation_count":10,"is_preprint":false},{"pmid":"23621172","id":"PMC_23621172","title":"Oncostatin M is a FIP1L1/PDGFRA-dependent mediator of cytokine production in chronic eosinophilic leukemia.","date":"2013","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/23621172","citation_count":10,"is_preprint":false},{"pmid":"17591942","id":"PMC_17591942","title":"A case of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia with a rare FIP1L1 breakpoint.","date":"2007","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/17591942","citation_count":10,"is_preprint":false},{"pmid":"25923837","id":"PMC_25923837","title":"Generalized Eruptive Histiocytosis Associated With FIP1L1-PDGFRA-Positive Chronic Eosinophilic Leukemia.","date":"2015","source":"JAMA dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25923837","citation_count":10,"is_preprint":false},{"pmid":"24460680","id":"PMC_24460680","title":"Complete and long-lasting cytologic and molecular remission of FIP1L1-PDGFRA-positive acute eosinophil myeloid leukaemia, treated with low-dose imatinib monotherapy.","date":"2014","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/24460680","citation_count":9,"is_preprint":false},{"pmid":"17701174","id":"PMC_17701174","title":"A multicenter analysis of the FIP1L1-alphaPDGFR fusion gene in Japanese idiopathic hypereosinophilic syndrome: an aberrant splicing skipping the alphaPDGFR exon 12.","date":"2007","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/17701174","citation_count":9,"is_preprint":false},{"pmid":"21302907","id":"PMC_21302907","title":"Comparative proteomic analysis of blood eosinophils reveals redox signaling modifications in patients with FIP1L1-PDGFRA-associated chronic eosinophilic leukemia.","date":"2011","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/21302907","citation_count":8,"is_preprint":false},{"pmid":"19338765","id":"PMC_19338765","title":"The FIP-1 like polyadenylation factor in trypanosomes and the structural basis for its interaction with CPSF30.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19338765","citation_count":8,"is_preprint":false},{"pmid":"19118897","id":"PMC_19118897","title":"Validation of a new three-color fluorescence in situ hybridization (FISH) method to detect CHIC2 deletion, FIP1L1/PDGFRA fusion and PDGFRA translocations.","date":"2008","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/19118897","citation_count":8,"is_preprint":false},{"pmid":"23232855","id":"PMC_23232855","title":"A case of nonleukemic myeloid sarcoma with FIP1L1-PDGFRA rearrangement: an unusual presentation of a rare disease.","date":"2013","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23232855","citation_count":8,"is_preprint":false},{"pmid":"18086564","id":"PMC_18086564","title":"Mechanisms for the proliferation of eosinophilic leukemia cells by FIP1L1-PDGFRalpha.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18086564","citation_count":7,"is_preprint":false},{"pmid":"24486648","id":"PMC_24486648","title":"Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis.","date":"2014","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/24486648","citation_count":7,"is_preprint":false},{"pmid":"18706197","id":"PMC_18706197","title":"FIP1L1-PDGFRalpha alone or with other genetic abnormalities reveals disease progression in chronic eosinophilic leukemia but good response to imatinib.","date":"2008","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18706197","citation_count":7,"is_preprint":false},{"pmid":"17988989","id":"PMC_17988989","title":"Successful imatinib treatment of cardiac involvement of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia followed by severe hepatotoxicity.","date":"2007","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/17988989","citation_count":7,"is_preprint":false},{"pmid":"29025601","id":"PMC_29025601","title":"A neoplasm with FIP1L1-PDGFRA fusion presenting as pediatric T-cell lymphoblastic leukemia/lymphoma without eosinophilia.","date":"2017","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29025601","citation_count":7,"is_preprint":false},{"pmid":"34249738","id":"PMC_34249738","title":"Myeloid Sarcoma Type of Acute Promyelocytic Leukemia With a Cryptic Insertion of RARA Into FIP1L1: The Clinical Utility of NGS and Bioinformatic Analyses.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34249738","citation_count":7,"is_preprint":false},{"pmid":"24764730","id":"PMC_24764730","title":"FIP1L1-PDGFRA-Positive Chronic Eosinophilic Leukemia: A Low-Burden Disease with Dramatic Response to Imatinib - A Report of 5 Cases from South India.","date":"2014","source":"Turkish journal of haematology : official journal of Turkish Society of Haematology","url":"https://pubmed.ncbi.nlm.nih.gov/24764730","citation_count":7,"is_preprint":false},{"pmid":"26457233","id":"PMC_26457233","title":"Refractory myeloid sarcoma with a FIP1L1-PDGFRA rearrangement detected by clinical high throughput somatic sequencing.","date":"2015","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26457233","citation_count":7,"is_preprint":false},{"pmid":"16496213","id":"PMC_16496213","title":"Fip1--an essential component of the Saccharomyces cerevisiae polyadenylation machinery is phosophorylated by protein kinase CK2.","date":"2006","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16496213","citation_count":6,"is_preprint":false},{"pmid":"16089297","id":"PMC_16089297","title":"FIP1L1-PDGFR alpha, a therapeutic target for the treatment of chronic eosinophilic leukemia.","date":"2005","source":"Verhandelingen - Koninklijke Academie voor Geneeskunde van Belgie","url":"https://pubmed.ncbi.nlm.nih.gov/16089297","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54080,"output_tokens":7730,"usd":0.139095,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17074,"output_tokens":5323,"usd":0.109223,"stage2_stop_reason":"end_turn"},"total_usd":0.248318,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"An interstitial deletion on chromosome 4q12 fuses FIP1L1 to PDGFRA, creating a constitutively activated tyrosine kinase (FIP1L1-PDGFRα) that transforms hematopoietic cells. The fusion kinase is inhibited by imatinib (IC50 ~3.2 nM). Resistance is conferred by a T674I point mutation in the PDGFRα kinase domain.\",\n      \"method\": \"Chromosomal analysis, RT-PCR, cell transformation assay (Ba/F3), in vitro kinase inhibition assay\",\n      \"journal\": \"The New England Journal of Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — constitutive kinase activity demonstrated in cell transformation assay, IC50 measured in vitro, resistance mutation confirmed at relapse, replicated across multiple subsequent studies\",\n      \"pmids\": [\"12660384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PKC412 (midostaurin) inhibits FIP1L1-PDGFRα, including the imatinib-resistant T674I mutant, in a murine bone marrow transplant model of FIP1L1-PDGFRα-induced myeloproliferative disease.\",\n      \"method\": \"Murine bone marrow transplantation model, in vitro proliferation assay with Ba/F3 cells transformed by FIP1L1-PDGFRα\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo murine model plus in vitro kinase inhibition, T674I resistance mechanism confirmed, replicated by subsequent work\",\n      \"pmids\": [\"12781364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human Fip1 (hFip1, encoded by FIP1L1) is an integral subunit of CPSF. It interacts with poly(A) polymerase (PAP) and contains an arginine-rich RNA-binding motif that preferentially binds U-rich sequence elements on pre-mRNA. Recombinant hFip1 is sufficient to stimulate in vitro polyadenylation activity of PAP in a U-rich element-dependent manner. hFip1, CPSF160, and PAP form a ternary complex in vitro.\",\n      \"method\": \"Co-immunoprecipitation, in vitro polyadenylation assay with recombinant proteins, RNA-binding assay, ternary complex reconstitution\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro polyadenylation, direct binding demonstrated, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"14749727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane (JM) domain of PDGFRα, not FIP1L1 itself. The FIP1L1 portion is completely dispensable for kinase activation in vitro and in vivo; truncation of PDGFRα between two conserved tryptophan residues in the JM domain is required for constitutive kinase activation and transforming potential. A complete JM domain is autoinhibitory, but this autoinhibition can be overcome by enforced homodimerization.\",\n      \"method\": \"Deletion mutagenesis, cell transformation assay, in vitro kinase assay, murine bone marrow transplantation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the USA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-function mutagenesis combined with in vitro and in vivo models, mechanistic conclusion clearly supported by multiple experimental approaches\",\n      \"pmids\": [\"16690743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast Fip1 (the ortholog of FIP1L1) directly interacts with poly(A) polymerase (Pap1) in a 1:1 complex. Fip1 is required for polyadenylation but not cleavage of pre-mRNA in vitro. Fip1 also directly interacts with RNA14, a subunit of cleavage factor I (CF I), through co-immunoprecipitation, thereby tethering Pap1 to CF I to confer substrate specificity.\",\n      \"method\": \"Two-hybrid assay, in vitro reconstitution of 1:1 complex, temperature-sensitive mutant analysis, in vitro 3'-end processing assay, co-immunoprecipitation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined 1:1 stoichiometry, genetic validation via ts-allele, co-IP for RNA14 interaction, foundational mechanistic study\",\n      \"pmids\": [\"7736590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Yeast Fip1 regulates poly(A) polymerase (Pap1) activity through multiple domains: residues 80–105 bind Pap1 and inhibit its activity by limiting RNA substrate access to Pap1's C-terminal RNA-binding domain (C-RBD); residues 206–220 interact with Yth1 (a CPSF subunit) and are required for specific polyadenylation; residues 105–206 help restrict RNA binding at the C-RBD of Pap1. The C-terminus of Fip1 relieves Fip1-mediated repression of Pap1.\",\n      \"method\": \"Domain deletion mutagenesis, in vitro binding assays, in vitro polyadenylation assay, yeast viability assay\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with multiple functional domains identified, in vitro mechanistic assays, viability confirming physiological relevance\",\n      \"pmids\": [\"11238938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sorafenib is a potent inhibitor of FIP1L1-PDGFRα (wild-type) and the imatinib-resistant FIP1L1-PDGFRα T674I mutant. It inhibits proliferation of transformed Ba/F3 cells and induces apoptosis of EOL-1 cells at nanomolar concentrations, confirmed by Western blot showing direct inhibition of FIP1L1-PDGFRα phosphorylation.\",\n      \"method\": \"In vitro proliferation assay (Ba/F3 cells), apoptosis assay (EOL-1), Western blot for phospho-PDGFRα\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct kinase inhibition shown by Western blot, cellular functional assays, replicated by subsequent clinical reports\",\n      \"pmids\": [\"16645167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FIP1L1-PDGFRα induces myeloproliferation in human CD34+ hematopoietic progenitors via activation of PI3K, ERK1/2, and STAT5 signaling pathways. Combined inhibition of PI3K and ERK1/2 significantly reversed FIP1L1-PDGFRα-induced colony formation. Dominant-negative STAT5 partially inhibited colony formation. FIP1L1 residues 30–233 contribute to STAT5 and Akt activation (but not p38/ERK1/2).\",\n      \"method\": \"Retroviral transduction of human CD34+ progenitors, cytokine-independent colony assay, dominant-negative STAT5 expression, pharmacological inhibitors of PI3K and ERK1/2, Western blot signaling analysis\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative, pharmacological inhibitors, deletion mutants) in primary human progenitor cells\",\n      \"pmids\": [\"17440089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of yeast poly(A) polymerase (Pap1) in complex with a peptide of Fip1 residues 80–105 at 2.6 Å resolution. The Fip1 peptide binds the outer surface of the C-terminal domain of Pap1. A Pap1 mutant (V498Y, C485R) designed from the structure cannot bind Fip1 but retains full polymerase activity and is lethal in yeast. Fip1 is largely disordered in the absence of Pap1.\",\n      \"method\": \"X-ray crystallography (2.6 Å), site-directed mutagenesis, yeast viability assay, analytical ultracentrifugation, circular dichroism, limited proteolysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis and functional validation, multiple orthogonal biophysical methods confirming Fip1 disorder\",\n      \"pmids\": [\"18537269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FIP1L1-PDGFRα and TEL-PDGFRβ fusion proteins escape ubiquitination and proteasomal degradation unlike their wild-type counterparts. Ubiquitination of FIP1L1-PDGFRα is markedly reduced despite Cbl phosphorylation. Protein stability of the fusion is critical for efficient stimulation of cell proliferation and STAT5 activation, demonstrated by an inducible destabilizing domain fusion experiment.\",\n      \"method\": \"Western blot for ubiquitination and protein levels in Ba/F3 cells and patient leukocytes, destabilizing domain (DD) fusion approach, STAT5 phosphorylation assay\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (ubiquitination, DD fusion, patient material) in single lab\",\n      \"pmids\": [\"19644140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FIP1L1-PDGFRα confers eosinophil lineage commitment on hematopoietic stem/progenitor cells by activating MEK1/2 and p38 MAPK more intensely than TEL-PDGFRβ. FIP1L1-PDGFRα augments expression of C/EBPα, GATA-1, and GATA-2 while suppressing PU.1 activity via Ras signaling. shRNA knockdown of C/EBPα, GATA-2, and dominant-negative GATA inhibited FIP1L1-PDGFRα-induced eosinophil development.\",\n      \"method\": \"Retroviral transduction of murine hematopoietic progenitor subsets, cytokine-independent replating assay, bone marrow transplantation, pharmacological MEK/p38 inhibition, shRNA knockdown, luciferase reporter for PU.1 activity, RT-PCR for transcription factor expression\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic knockdown, pharmacological inhibition, luciferase reporter) across defined progenitor subsets with clear mechanistic pathway placement\",\n      \"pmids\": [\"19147501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FIP1L1-PDGFRα D842V mutation is pan-resistant to sorafenib, imatinib, dasatinib, and PKC412 in vitro. This mutant emerged clinically under sorafenib therapy for T674I-mutant disease, and was identified as a major sorafenib-resistant mutant by ENU mutagenesis screen.\",\n      \"method\": \"ENU-mutagenesis screen, in vitro proliferation assays with Ba/F3 cells expressing D842V mutant, clinical case report with molecular confirmation\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ENU screen plus in vitro validation; single lab but multiple experimental approaches\",\n      \"pmids\": [\"19212337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"hFip1 (FIP1L1 protein) interacts specifically with the U-rich upstream element of the HPV-16 early polyadenylation signal and enhances polyadenylation at that site.\",\n      \"method\": \"RNA pulldown/interaction assay (in vitro binding), polyadenylation signal analysis, deletion mapping\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding demonstrated but limited to a single pulldown approach; consistent with established U-rich binding function from EMBO J 2004\",\n      \"pmids\": [\"15767428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Yeast Fip1 contains a flexible linker region (middle of the protein) required for efficient mRNA polyadenylation. Removal or replacement of the linker reduces polyadenylation efficiency. The linker provides a platform for interactions with other polyadenylation machinery components. A fusion protein of Pap1 directly tethered to Fip1 is fully functional, and direct tethering of Pap1 to RNA increases the rate of poly(A) addition.\",\n      \"method\": \"In vitro polyadenylation assay, yeast viability assay, deletion/replacement mutagenesis, Pap1-Fip1 fusion protein functional test\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro polyadenylation reconstitution with defined deletion mutants plus yeast in vivo complementation, multiple orthogonal approaches\",\n      \"pmids\": [\"21282348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fip1 is essential for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Fip1 promotes stem cell maintenance by activating ESC-specific alternative polyadenylation (APA) profiles through Fip1-RNA interactions and APA site distance. Loss of Fip1 disrupts expression of critical self-renewal factors.\",\n      \"method\": \"Genetic knockout/knockdown in mouse ESCs, RNA-seq/PAC-seq for APA profiling, somatic reprogramming assay, self-renewal colony assay\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific phenotypic readout (self-renewal failure), genome-wide APA mapping, rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"24596251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FIP1L1-PDGFRα activates JAK2, and JAK2 is required for FIP1L1-PDGFRα-driven cellular proliferation and migration. JAK2 inhibition (siRNA or AG490) in EOL-1 and primary FIP1L1-PDGFRα+ CEL cells reduces proliferation, induces apoptosis, and blocks IL-5-induced migration. JAK2 mediates STAT3 (but not STAT5) activation and also activates PI3K/Akt and NF-κB downstream.\",\n      \"method\": \"siRNA knockdown of JAK2, pharmacological inhibition (AG490), Western blot for signaling, proliferation and apoptosis assays, migration assay, patient primary cells\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological approaches in cell lines and patient primary cells, but single lab\",\n      \"pmids\": [\"22523564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FIP1L1-PDGFRα activates NF-κB via PI3K. NF-κB is required for FIP1L1-PDGFRα-driven eosinophil differentiation from human CD34+ progenitors, including expression of IL-5Rα and eosinophil peroxidase. Bortezomib and the IκB kinase inhibitor BMS-345541 block proliferation of EOL-1 cells.\",\n      \"method\": \"Lentiviral transduction of human CD34+ progenitors, PI3K inhibitor, dominant-negative IκB expression, pharmacological NF-κB inhibition, gene expression microarray\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative and pharmacological approaches in human primary cells; single lab, multiple complementary methods\",\n      \"pmids\": [\"22271894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SHP2 tyrosine phosphatase binds directly to tyrosine 720 of FIP1L1-PDGFRα and is required for ERK signaling and cell transformation. Mutation of Y720 or SHP2 knockdown reduces proliferation and ERK (but not STAT5) signaling in Ba/F3 cells and in human CD34+ progenitors. SHP2 is not required for wild-type PDGFR-driven ERK activation, indicating an oncogene-specific shift in SHP2 function.\",\n      \"method\": \"Site-directed mutagenesis (12 tyrosine residues), SHP2 siRNA knockdown, in vivo murine myeloproliferation assay, human CD34+ progenitor assay, co-immunoprecipitation (SHP2 binding to Y720)\",\n      \"journal\": \"Molecular Oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct co-IP of SHP2 binding to Y720, mutagenesis, siRNA knockdown in multiple cell systems including primary human progenitors, and in vivo validation\",\n      \"pmids\": [\"24618081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In FIP1L1-RARA fusion, the FIP1 motif of FIP1L1 is required for homodimerization and transcriptional repressor activity. In FIP1L1-PDGFRα, the C-terminal PDGFRα portion can form homodimers independently, making FIP1L1 dispensable for constitutive kinase activation, but FIP1L1 contributes to complete IL-3 independence of transformed cells.\",\n      \"method\": \"Deletion mutant analysis, hematopoietic cell transformation assay (BAF-B03), cytokine independence assay\",\n      \"journal\": \"Annals of Hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutant series with functional readout in cell lines; single lab, no structural confirmation\",\n      \"pmids\": [\"24763514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The F604S mutation in FIP1L1-PDGFRα stabilizes the fusion protein by creating a binding site for the SHP-2 phosphatase domain, reducing autophosphorylation and consequently reducing SRC activation. SRC normally promotes FIP1L1-PDGFRα degradation via CBL ubiquitination; reduced SRC activation thus prolongs protein half-life. SRC inhibition or knockdown phenocopies the protein stabilization seen with F604S.\",\n      \"method\": \"Pulse-chase protein stability assay, site-directed mutagenesis, co-immunoprecipitation (SHP-2 binding), SRC inhibition and knockdown, Western blot for autophosphorylation and CBL\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct co-IP demonstrating SHP-2 binding, pulse-chase for stability, SRC siRNA and inhibitor confirming mechanism, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25761934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human CPSF30 ZF4-ZF5 binds hFip1 with 1:2 stoichiometry (one hFip1 molecule per zinc finger, ZF4 and ZF5). Crystal structure at 1.9 Å reveals a conserved binding mode for each ZF. ZF4 has higher affinity for hFip1 (Kd = 1.8 nM). Two copies of the catalytic module of PAP are recruited by the CPSF30-hFip1 complex in vitro, and both hFip1 binding sites in CPSF30 can support polyadenylation.\",\n      \"method\": \"X-ray crystallography (1.9 Å), fluorescence polarization binding assay, mutagenesis, in vitro polyadenylation assay\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus quantitative binding assay plus in vitro functional polyadenylation assay, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33122294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Fip1, within the reconstituted ~850 kDa CPF complex, anchors poly(A) polymerase Pap1 via an interaction with zinc finger 4 of Yth1. The intrinsically disordered region (IDR) of Fip1 connecting the Yth1- and Pap1-binding sites remains highly dynamic within CPF, as demonstrated by NMR spectroscopy on selectively labeled Fip1 incorporated into the recombinant complex.\",\n      \"method\": \"Fully recombinant CPF reconstitution, NMR spectroscopy (selective isotope labeling), genetic interaction (Fip1-Yth1 ZF4 interaction mapped)\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of recombinant megadalton complex, NMR characterization of dynamics, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"34593603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPSF contains two copies of hFip1, each binding to ZF4 and ZF5 of CPSF30 (crystal structures reported). The two hFip1 copies are functionally redundant in recruiting one copy of PAP, increasing processivity of RNA polyadenylation. hFip1 interacts with CstF77 via a short motif in its N-terminal 'acidic' region; CstF77 competitively inhibits CPSF-dependent PAP recruitment and polyadenylation.\",\n      \"method\": \"X-ray crystallography (hFip1-CPSF30 and hFip1-CstF77 complexes), in vitro polyadenylation assay, mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two crystal structures plus in vitro polyadenylation functional assays plus mutagenesis, multiple orthogonal methods validating structural findings\",\n      \"pmids\": [\"36073787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FIP1L1 (hFip1) promotes 3'UTR shortening of NLRP3 mRNA via its arginine-rich domain binding to the proximal poly(A) site (pPAS) of NLRP3 mRNA, thereby upregulating NLRP3 expression and amplifying inflammation in kidney injury. FIP1L1 is upregulated by oxidative stress and is required for oxidative stress-induced NLRP3 upregulation.\",\n      \"method\": \"siRNA knockdown (in vitro and in vivo UUO/IRI models), RNA-IP (FIP1L1 binding to NLRP3 pPAS), 3'RACE/APA profiling, Western blot, inflammation/fibrosis functional assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP for direct binding plus functional KD in vivo; single lab, two orthogonal methods\",\n      \"pmids\": [\"34011928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Yeast Fip1 is phosphorylated in vitro by protein kinase CK2 (but not CK1) at serine residues 73 and 77, as identified by MALDI-MS. CK2α' and holoenzyme phosphorylate Fip1 with Km of ~1.3–1.4 µM.\",\n      \"method\": \"In vitro kinase assay with recombinant CK2, MALDI-MS identification of phosphorylation sites\",\n      \"journal\": \"Molecular and Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro phosphorylation assay with site identification by MS, but functional consequence not established and single lab\",\n      \"pmids\": [\"16496213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FIP1L1-PDGFRα induces proliferation of EOL-1 eosinophilic leukemia cells through upregulation of c-Myc via ERK and JNK signaling pathways. Imatinib inhibits proliferation and decreases c-Myc, phospho-ERK, and phospho-JNK. MEK inhibitor (U0126) and JNK inhibitor (SP600125) also reduce c-Myc expression and proliferation. FIP1L1-PDGFRα is not required for inhibition of eosinophil differentiation.\",\n      \"method\": \"Western blot, pharmacological inhibitors (imatinib, U0126, SP600125), RT-PCR for c-Myc in EOL-1 cells\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitors with multiple signaling readouts; single lab without genetic validation of the pathway\",\n      \"pmids\": [\"18086564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FIP1L1-PDGFRα (F/P) upregulates oncostatin M (OSM) expression in a STAT5-dependent manner. OSM secreted by neoplastic eosinophils stimulates stromal cell proliferation and upregulates SDF-1/CXCL12 production in fibroblasts, which in turn induces migration of EOL-1 cells—constituting a paracrine loop contributing to tissue fibrosis and eosinophil accumulation.\",\n      \"method\": \"Lentiviral F/P transduction of cell lines, doxycycline-inducible F/P in Ba/F3, STAT5 inhibition, immunohistochemistry of patient material, gene expression analysis, proliferation and chemotaxis assays\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system plus patient tissue validation plus functional migration assay; single lab\",\n      \"pmids\": [\"23621172\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FIP1L1 encodes two functionally distinct proteins: (1) as the canonical mRNA 3'-end processing factor hFip1, it is an intrinsically disordered, multivalent scaffold subunit of CPSF that directly binds PAP (recruiting it to the cleavage/polyadenylation complex via CPSF30 ZF4/ZF5), stimulates PAP activity in a U-rich element-dependent manner, interacts with CstF77 to competitively regulate PAP recruitment, and controls alternative polyadenylation to regulate gene expression in stem cell self-renewal and disease contexts; (2) as the N-terminal fusion partner in FIP1L1-PDGFRα (generated by cryptic del(4)(q12)), FIP1L1 itself is dispensable for kinase activation—constitutive activity arises from disruption of the PDGFRα juxtamembrane autoinhibitory domain—but the fusion escapes ubiquitination/degradation, signals through PI3K/ERK/STAT5/JAK2/NF-κB to drive eosinophil lineage commitment via C/EBPα, GATA-2, and Ras/MEK cascades, and is inhibited by imatinib with resistance conferred by T674I, D842V, S601P, or F604S mutations in the kinase domain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FIP1L1 encodes hFip1, an intrinsically disordered, multivalent scaffold subunit of the cleavage and polyadenylation specificity factor (CPSF) that couples poly(A) polymerase (PAP) to pre-mRNA 3'-end processing [#2, #4]. hFip1 directly binds PAP and an arginine-rich motif preferentially recognizes U-rich pre-mRNA elements, and recombinant hFip1 is sufficient to stimulate PAP polyadenylation activity in a U-rich-element-dependent manner [#2]. Within CPSF, two copies of hFip1 are tethered through the ZF4 and ZF5 zinc fingers of CPSF30, and these copies act redundantly to recruit PAP and increase polyadenylation processivity, while an N-terminal acidic motif of hFip1 binds CstF77 to competitively modulate PAP recruitment [#20, #22]. The disordered linker connecting the CPSF-anchoring and PAP-binding sites remains highly dynamic within the assembled complex, consistent with a flexible-tether mechanism that positions PAP near RNA [#13, #21]. Through control of alternative polyadenylation, hFip1 is essential for embryonic stem cell self-renewal and somatic reprogramming [#14] and drives 3'UTR shortening of NLRP3 mRNA to amplify inflammation under oxidative stress [#23]. Independently, FIP1L1 is the N-terminal partner of the FIP1L1-PDGFR\\u03b1 fusion generated by a chromosome 4q12 deletion, a constitutively active tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib, with the T674I and D842V kinase-domain mutations conferring resistance [#0, #11]; this fusion underlies a myeloproliferative/chronic eosinophilic leukemia phenotype. Constitutive activation arises from disruption of the PDGFR\\u03b1 juxtamembrane autoinhibitory domain rather than from FIP1L1 itself, which is dispensable for kinase activation [#3]. The fusion escapes ubiquitination and proteasomal degradation, and signals through PI3K/ERK/STAT5, JAK2, SHP2, and NF-\\u03baB to drive eosinophil lineage commitment via C/EBP\\u03b1 and GATA-2 [#7, #9, #10, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding mechanism: Fip1 physically links poly(A) polymerase to the 3'-end processing machinery, answering how PAP is recruited and made substrate-specific.\",\n      \"evidence\": \"Two-hybrid, in vitro reconstitution of a 1:1 Fip1-Pap1 complex, ts-mutant and 3'-processing assays in yeast\",\n      \"pmids\": [\"7736590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Fip1-Pap1 interface not defined\", \"Human ortholog function not yet shown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Dissected Fip1 into discrete functional domains, showing it both inhibits and directs PAP activity through separable Pap1-binding, Yth1-binding, and RNA-restricting regions.\",\n      \"evidence\": \"Domain deletion mutagenesis, in vitro polyadenylation, and yeast viability assays\",\n      \"pmids\": [\"11238938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the C-terminus relieves repression not structurally resolved\", \"In vivo relevance of individual domains in mammals untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed an entirely distinct disease-driving role: a 4q12 deletion fuses FIP1L1 to PDGFRA to create a constitutively active, imatinib-sensitive kinase, defining the molecular basis of a myeloproliferative disease.\",\n      \"evidence\": \"Chromosomal analysis, RT-PCR, Ba/F3 transformation, in vitro kinase inhibition; plus murine BMT model with PKC412\",\n      \"pmids\": [\"12660384\", \"12781364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of the FIP1L1 portion to activation not yet resolved\", \"Resistance mechanisms beyond T674I unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified human hFip1 as an integral CPSF subunit that binds PAP and U-rich RNA and stimulates polyadenylation, establishing functional conservation of the yeast mechanism in humans.\",\n      \"evidence\": \"Co-IP, recombinant in vitro polyadenylation, RNA-binding and ternary complex reconstitution\",\n      \"pmids\": [\"14749727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry within CPSF not determined\", \"Genome-wide targets and APA roles unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved that FIP1L1-PDGFR\\u03b1 activation derives from loss of the PDGFR\\u03b1 juxtamembrane autoinhibition, not from FIP1L1, clarifying the oncogenic mechanism.\",\n      \"evidence\": \"Deletion mutagenesis, in vitro kinase assay, cell transformation, murine BMT\",\n      \"pmids\": [\"16690743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why the fusion is favored over other JM-disrupting events not addressed\", \"Role of FIP1L1 sequences in fine-tuning signaling left open\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified CK2 as a kinase phosphorylating yeast Fip1, raising the possibility of post-translational regulation of polyadenylation.\",\n      \"evidence\": \"In vitro CK2 kinase assay with MALDI-MS site identification\",\n      \"pmids\": [\"16496213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of S73/S77 phosphorylation not established\", \"Phosphorylation not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped the proliferative signaling output of FIP1L1-PDGFR\\u03b1 to PI3K, ERK1/2, and STAT5 in primary human progenitors, defining therapeutically relevant nodes.\",\n      \"evidence\": \"CD34+ retroviral transduction, dominant-negative STAT5, PI3K/ERK inhibitors, colony assays; c-Myc via ERK/JNK in EOL-1\",\n      \"pmids\": [\"17440089\", \"18086564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each pathway to in vivo disease unclear\", \"Connection between signaling and lineage choice not yet made\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the structural basis of Fip1-PAP recognition and confirmed Fip1 is intrinsically disordered absent its partner.\",\n      \"evidence\": \"X-ray crystallography of Pap1-Fip1(80-105), structure-guided mutagenesis, yeast viability, CD and ultracentrifugation\",\n      \"pmids\": [\"18537269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformation of full-length Fip1 within CPSF not resolved\", \"Human complex architecture not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Explained why FIP1L1-PDGFR\\u03b1 accumulates: it escapes ubiquitin-mediated degradation, and its protein stability is required for proliferation and STAT5 activation.\",\n      \"evidence\": \"Ubiquitination Western blots, destabilizing-domain fusion, patient leukocytes\",\n      \"pmids\": [\"19644140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular reason for reduced ubiquitination despite Cbl phosphorylation unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected fusion signaling to cell fate, showing FIP1L1-PDGFR\\u03b1 enforces eosinophil lineage commitment via MEK/p38, C/EBP\\u03b1 and GATA-2 induction, and PU.1 suppression.\",\n      \"evidence\": \"Murine progenitor transduction, BMT, MEK/p38 inhibitors, shRNA, PU.1 luciferase reporter; plus D842V pan-resistance ENU screen\",\n      \"pmids\": [\"19147501\", \"19212337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of induced factors not mapped\", \"Why eosinophil-specific among myeloid fates incompletely defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the signaling network to JAK2 and PI3K-dependent NF-\\u03baB as required effectors of proliferation, migration, and eosinophil differentiation.\",\n      \"evidence\": \"JAK2 siRNA/AG490 and dominant-negative I\\u03baB/NF-\\u03baB inhibition in EOL-1, primary CEL cells, and CD34+ progenitors\",\n      \"pmids\": [\"22523564\", \"22271894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among JAK2, PI3K, NF-\\u03baB nodes not fully ordered\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined an oncogene-specific role for SHP2 binding to phosphotyrosine 720 of the fusion in driving ERK signaling and transformation.\",\n      \"evidence\": \"Tyrosine mutagenesis, SHP2 co-IP and siRNA, Ba/F3, CD34+ progenitors, murine model\",\n      \"pmids\": [\"24618081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why SHP2 dependence is fusion-specific versus wild-type PDGFR not mechanistically explained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established hFip1 as essential for stem cell identity by controlling ESC-specific alternative polyadenylation, linking the polyadenylation scaffold to cell-fate gene expression.\",\n      \"evidence\": \"Mouse ESC knockout/knockdown, PAC-seq/RNA-seq APA profiling, reprogramming and self-renewal assays; FIP1 motif homodimerization in fusion contexts\",\n      \"pmids\": [\"24596251\", \"24763514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which APA target transcripts drive self-renewal not fully resolved\", \"How Fip1-RNA interactions set APA site choice mechanistically unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved a drug-resistance mechanism in which the F604S mutation stabilizes the fusion by recruiting SHP-2 to dampen autophosphorylation and SRC-driven CBL ubiquitination.\",\n      \"evidence\": \"Pulse-chase stability, mutagenesis, SHP-2 co-IP, SRC inhibition/knockdown\",\n      \"pmids\": [\"25761934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of SRC-CBL turnover control across resistance mutants untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Delivered the structural and functional architecture of the human CPSF-hFip1 module: two redundant hFip1 copies on CPSF30 ZF4/ZF5 recruit PAP for processivity, and an hFip1 acidic motif binds CstF77 to competitively regulate PAP recruitment.\",\n      \"evidence\": \"X-ray crystallography of hFip1-CPSF30 and hFip1-CstF77, fluorescence polarization, in vitro polyadenylation, mutagenesis; recombinant CPF NMR showing IDR dynamics; yeast linker analysis\",\n      \"pmids\": [\"33122294\", \"36073787\", \"34593603\", \"21282348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CstF77 competition is regulated during processing in cells unclear\", \"Whether the two hFip1 sites are differentially used on specific transcripts unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a disease-relevant APA function for hFip1 in inflammation, shortening NLRP3 3'UTR to upregulate NLRP3 under oxidative stress.\",\n      \"evidence\": \"siRNA in vitro/in vivo kidney injury models, RNA-IP at NLRP3 proximal poly(A) site, 3'RACE/APA profiling; plus STAT5-dependent OSM/CXCL12 paracrine loop in fusion disease\",\n      \"pmids\": [\"34011928\", \"23621172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breadth of inflammation-relevant APA targets beyond NLRP3 unknown\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two functionally distinct activities of FIP1L1 \\u2014 the CPSF polyadenylation scaffold and the oncogenic fusion N-terminus \\u2014 are regulated in physiological versus disease contexts, including the in vivo determinants of APA target selection and the full set of post-translational controls, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No comprehensive map of hFip1-controlled APA targets in normal tissues\", \"Functional role of CK2 phosphorylation undefined\", \"Mechanism integrating signaling, stability, and lineage output in fusion disease incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 12, 23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 20, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5, 22]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 14, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 14, 20, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 4, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 17, 16]}\n    ],\n    \"complexes\": [\"CPSF\", \"CPF (yeast cleavage and polyadenylation factor)\"],\n    \"partners\": [\"PAP/Pap1\", \"CPSF30\", \"CstF77\", \"CPSF160\", \"YTH1\", \"RNA14\", \"PDGFRA\", \"SHP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}