{"gene":"CRLF2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2009,"finding":"CRLF2 rearrangement (P2RY8-CRLF2 fusion) co-operates with activating JAK2 mutations to cause constitutive JAK-STAT activation and cytokine-independent growth; expression of P2RY8-CRLF2 together with mutated Jak2 in Ba/F3 cells overexpressing IL-7Rα resulted in constitutive Jak-Stat activation and cytokine-independent proliferation.","method":"Ba/F3 cell transformation assay; retroviral co-expression of P2RY8-CRLF2 and mutant Jak2","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-based functional reconstitution replicated across multiple independent groups (PMID 19838194, 19641190, 19965641)","pmids":["19838194"],"is_preprint":false},{"year":2009,"finding":"CRLF2 overexpression activates the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation, indicating a causal role in lymphoid transformation.","method":"Retroviral transduction of primary B-cell progenitors with CRLF2; JAK-STAT phosphorylation assays; proliferation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional experiment in primary cells, replicated by multiple groups","pmids":["19641190"],"is_preprint":false},{"year":2009,"finding":"CRLF2 encodes a type I cytokine receptor subunit that, when overexpressed, can substitute for IL-3 signaling in a functional screen; CRLF2 acts as the key scaffold for mutant JAK2 signaling in B-ALL, since all 22 B-ALLs with mutant JAK2 overexpressed CRLF2.","method":"Functional mRNA screen for IL-3 signaling substitution; Ba/F3 cytokine-independent growth assay; phospho-JAK2 analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays in single study with broad patient sample validation","pmids":["20018760"],"is_preprint":false},{"year":2009,"finding":"A gain-of-function CRLF2 F232C mutation promotes constitutive receptor dimerization and cytokine-independent growth in Ba/F3 cells; this differs mechanistically from WT CRLF2/mutant JAK2 signaling (which involves JAK2 phosphorylation) versus CRLF2 F232C (which does not involve JAK2 phosphorylation).","method":"Ba/F3 cytokine-independent growth assay; phospho-JAK2 Western blotting; site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with functional readout, replicated in patient samples across multiple groups","pmids":["20018760","19965641"],"is_preprint":false},{"year":2009,"finding":"CRLF2 and mutated JAK2 cooperate in conferring cytokine-independent growth to BaF3 pro-B cells; the F232C mutation in CRLF2 was identified as an activating somatic mutation.","method":"Ba/F3 transformation assay; retroviral co-expression of CRLF2 variants and mutant JAK2","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional cell-based assay replicated across multiple independent studies","pmids":["19965641"],"is_preprint":false},{"year":2001,"finding":"CRLF2 was identified as a type I cytokine receptor with an extracellular domain containing two fibronectin type III-like domains, four conserved cysteine residues, a WSXWS box-like motif, and an intracellular domain containing box 1 and box 2-like motifs; the gene is located in the pseudoautosomal region Xp22.3/Yp11.3.","method":"cDNA cloning from T-lymphocyte library; sequence analysis; FISH mapping","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cDNA cloning and FISH, replicated by independent group (PMID 11237741)","pmids":["11474172","11237741"],"is_preprint":false},{"year":2001,"finding":"CRLF2 (CRL2) is a type I transmembrane cytokine receptor preferentially expressed by dendritic cells and activated monocytes; its expression is upregulated by LPS stimulation of monocytes; the intracellular domain contains a box 1 motif and a conserved tyrosine potentially binding signal-transducing molecules.","method":"cDNA library screening; RT-PCR; Northern blot; LPS stimulation; Ba/F3 transfection with FLAG-tagged CRLF2; immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — expression characterization combined with transfection and immunoprecipitation; single lab","pmids":["11237741"],"is_preprint":false},{"year":2002,"finding":"TSLPR (CRLF2) forms a heterodimeric complex with the IL-7 receptor alpha chain to form the functional receptor for TSLP; the WSXWX motif is conserved across mouse, rat, and human TSLPR; alternative splicing produces two functional receptor variants in mice.","method":"Cloning; sequence alignment; zooblot; alternative splice variant analysis; receptor reconstitution assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional receptor reconstitution and structural characterization, single study","pmids":["11891057"],"is_preprint":false},{"year":2010,"finding":"TSLP-dependent cell proliferation requires at least one cytoplasmic tyrosine residue in either IL-7Rα or CRLF2; the single tyrosine residue in human CRLF2 alone is NOT required for TSLP-dependent proliferation; tyrosine residues in IL-7Rα and CRLF2 play redundant roles in TSLP-mediated growth signaling.","method":"Site-directed mutagenesis of IL-7Rα and CRLF2 cytoplasmic tyrosines; Ba/F3 TSLP-dependent proliferation assay","journal":"BMC immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional readout, single lab","pmids":["20144186"],"is_preprint":false},{"year":2012,"finding":"CRLF2 signaling through three distinct mechanisms (TSLP stimulation, CRLF2 F232C mutation, and CRLF2/mutant JAK2) differs at the level of intracellular tyrosines: CRLF2 F232C requires intracellular tyrosine Y368, while TSLP- or mutant JAK2-driven signaling does not; all three modes require the CRLF2 box1 domain and intracellular tryptophan W286.","method":"Domain mutation analysis; Ba/F3 proliferation assay; global quantitative phosphotyrosine analysis; Western blotting","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional readout plus quantitative phosphoproteomics, single lab, multiple orthogonal methods","pmids":["22915648"],"is_preprint":false},{"year":2012,"finding":"CRLF2-rearranged ALL exhibits elevated basal pJAK2, pSTAT5, and pS6; TSLP stimulation of these leukemias induces robust JAK/STAT and PI3K/mTOR pathway signaling; JAK inhibition also abrogates PI3K/mTOR pathway phosphorylation, indicating interconnection between these signaling networks.","method":"Phospho-flow cytometry of primary ALL samples; TSLP stimulation assays; JAK inhibitor treatment with pathway readout","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — analysis of large numbers of primary patient samples with multiple pathway readouts, multiple orthogonal inhibitor experiments","pmids":["22685175"],"is_preprint":false},{"year":2015,"finding":"TSLP stimulates human CRLF2-overexpressing ALL via JAK/STAT5 and PI3K/AKT/mTOR pathways; mouse TSLP does NOT activate these downstream pathways in human CRLF2-rearranged ALL, demonstrating species-specific ligand–receptor interaction.","method":"TSLP stimulation of patient-derived xenograft samples; JAK/STAT5 and PI3K/AKT/mTOR phosphorylation assays; comparison of human vs. mouse TSLP","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct signaling assays in patient-derived cells, single lab, includes a functionally informative negative result","pmids":["26611474"],"is_preprint":false},{"year":2015,"finding":"TSLP stimulates platelet activation and thrombus formation via a TSLPR-dependent PI3K/Akt signaling pathway; TSLPR is expressed on murine platelets, and TSLPR-deficient platelets show defective aggregation, secretion, and in vivo thrombus formation.","method":"Western blotting; flow cytometry; TSLPR knockout mice; perfusion chambers; FeCl3 carotid artery thrombosis model; PI3K inhibitor assays","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype with defined signaling mechanism, single lab","pmids":["25591759"],"is_preprint":false},{"year":2016,"finding":"Ikaros (IKZF1-encoded protein) directly binds the CRLF2 promoter and represses CRLF2 transcription; CK2 inhibitor increases Ikaros binding to the CRLF2 promoter and suppresses CRLF2 expression in an Ikaros-dependent manner; this repression is associated with increased H3K9me3 histone modifications at the CRLF2 promoter.","method":"ChIP assay; CK2 inhibitor treatment; siRNA knockdown; H3K9me3 ChIP in ALL cell lines and primary cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional validation, multiple cell types, single lab","pmids":["27391346"],"is_preprint":false},{"year":2021,"finding":"HMGN1 overexpression in combination with P2RY8-CRLF2 in Ba/F3 cells results in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development; HMGN1 knockout mitigates CRLF2-rearranged leukemia burden in vivo.","method":"Ba/F3 transformation assay; inducible CRISPR/Cas9 knockout xenograft model; in vivo engraftment studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell transformation assay combined with in vivo KO model, single lab","pmids":["34857887"],"is_preprint":false},{"year":2022,"finding":"CRLF2 overexpression in Dp16 (Down syndrome model) B-progenitor cells results in enhanced immature B-lymphoid colony development and reduced B-cell differentiation, associated with a gene expression signature of E2F signaling; PI3K/mTOR and pan-CDK inhibitors show cytotoxicity in CRLF2-rearranged B-ALL.","method":"Dp16 mouse model; colony assays; gene expression profiling; inhibitor cytotoxicity assays in cell lines and patient samples","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with defined cellular phenotype and gene expression pathway identification, single lab","pmids":["35306048"],"is_preprint":false},{"year":2019,"finding":"CRLF2-rearranged Ph-like ALL leukemia cells demonstrate relative glucocorticoid resistance; inhibition of MEK (trametinib) or Akt (MK2206), but NOT JAK inhibition (ruxolitinib), is sufficient to augment glucocorticoid sensitivity, indicating that MAPK/Akt rather than JAK-STAT signaling mediates GC resistance downstream of CRLF2.","method":"Patient-derived xenograft GC sensitivity assays; targeted inhibitor studies with MEK, Akt, and JAK inhibitors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PDX-based functional experiment with pathway dissection via specific inhibitors, single lab","pmids":["31318944"],"is_preprint":false},{"year":2021,"finding":"JAK-directed PROTACs (proteolysis-targeting chimeras) degrade JAKs and potently kill CRLF2-rearranged ALL cell lines; solving crystal structures of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled rational PROTAC design; dual JAK/GSPT1-degrading PROTACs were most potent, with JAK2-degrading, GSPT1-sparing PROTACs also efficacious in kinase-driven xenografts.","method":"Crystal structure determination of JAK2-inhibitor complexes; PROTAC synthesis and testing; cell viability assays; xenograft models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with rational drug design, in vitro and in vivo validation, multiple PROTACs tested","pmids":["34110416"],"is_preprint":false},{"year":2022,"finding":"Genome-wide CRISPR-Cas9 dropout screens showed that STAT5A, STAT5B, and STAT3 are largely dispensable for IgH-CRLF2-rearranged ALL cell survival, while CRLF2, IL7RA, JAK1/2, and RAS signaling regulators (particularly CRKL) are critical; CRKL depletion enhances ruxolitinib sensitivity in RAS wild-type cells.","method":"Genome-wide CRISPR-Cas9 dropout screen; sgRNA fitness analysis; CRKL depletion experiments","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide functional screen with specific mechanistic follow-up, single lab","pmids":["34587248"],"is_preprint":false},{"year":2022,"finding":"High-dose TSLP induced apoptosis and loss of CRLF2 receptor expression in CRLF2 B-ALL cell lines in vitro, and prevented engraftment/prolonged survival in patient-derived xenograft mice; mechanistically, high TSLP doses caused receptor downregulation and loss of downstream CRLF2 signaling.","method":"In vitro cell line apoptosis assay; patient-derived xenograft in vivo model; receptor surface expression by flow cytometry; signaling pathway Western blotting","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with mechanistic signaling readout, single lab","pmids":["36613920"],"is_preprint":false},{"year":2023,"finding":"CRLF2-rearranged leukemia treated with ruxolitinib upregulates BCL6, which suppresses TP53 and pro-apoptotic molecules (FAS, TNFRSF10B, BID, BAX, BAK, PUMA, NOXA), conferring resistance; BCL6 inhibition combined with ruxolitinib restores TP53 expression, enhances apoptosis, and prolongs survival in xenografted mice.","method":"Gene expression analysis post-ruxolitinib treatment; BCL6 inhibitor (FX1) experiments; Western blotting for TP53 and apoptotic markers; xenograft survival assay","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with in vitro and in vivo validation, single lab","pmids":["36005560"],"is_preprint":false},{"year":2018,"finding":"In CRLF2-overexpressing B-ALL, a coordinated signaling network downstream of CRLF2 involves co-activation of JAK/STAT, PI3K, and CREB pathways; this network can be more effectively disrupted by SRC/ABL inhibition than by single-agent JAK or PI3K inhibition.","method":"Single-cell mass cytometry (CyTOF) on 15 primary patient samples; SRC/ABL inhibitor functional assays including in MRD cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-cell mass cytometry with inhibitor validation in primary samples, single lab","pmids":["29796158"],"is_preprint":false},{"year":2020,"finding":"TSLP stimulation of CRLF2-rearranged Ph-like ALL cells activates JAK1, JAK2, STAT5, ERK1/2, IGF1R, and FGFR1 phosphotyrosine signaling, as well as the Rap1 signaling pathway; phosphotyrosine profiling identified IGF1R and FGFR1 as novel TSLP-activated kinases in this context.","method":"Phosphotyrosine (P-Tyr) profiling with SILAC; TSLP stimulation of CRLF2-rearranged cell lines; tyrosine kinase inhibitor synergy assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative phosphoproteomics with SILAC, single lab, two cell line models","pmids":["32801162"],"is_preprint":false}],"current_model":"CRLF2 (TSLPR) encodes a type I cytokine receptor subunit that heterodimerizes with IL-7Rα to form the TSLP receptor; overexpression or activating mutations (F232C causing constitutive dimerization; co-occurring JAK1/2 mutations) drive constitutive JAK/STAT and PI3K/mTOR signaling to promote cytokine-independent B-cell progenitor proliferation and leukemogenesis, with downstream pathway activation depending on the specific oncogenic mechanism (TSLP-ligand vs. F232C vs. mutant JAK2), and CRLF2 expression is transcriptionally repressed by Ikaros (IKZF1) via H3K9me3 deposition at its promoter."},"narrative":{"mechanistic_narrative":"CRLF2 (TSLPR) encodes a type I cytokine receptor subunit bearing two fibronectin type III-like domains, a WSXWS-like motif, and intracellular box1/box2 motifs that heterodimerizes with the IL-7 receptor alpha chain to form the functional receptor for TSLP [PMID:11474172, PMID:11237741, PMID:11891057]. Originally characterized as a receptor expressed by dendritic cells and activated monocytes whose surface levels rise upon LPS stimulation [PMID:11237741], CRLF2 is best defined mechanistically as a driver of B-cell progenitor leukemogenesis: rearrangement (P2RY8-CRLF2) or overexpression activates the JAK-STAT pathway and confers cytokine-independent proliferation, cooperating with activating JAK2 mutations and acting as the obligate scaffold for mutant JAK2 signaling in B-ALL [PMID:19838194, PMID:19641190, PMID:20018760]. An activating F232C mutation drives constitutive receptor dimerization and growth through a mechanism distinct from TSLP- or mutant-JAK2-driven signaling, with the three modes differing in their dependence on specific intracellular tyrosines (F232C requires Y368) while all require the box1 domain and intracellular tryptophan W286 [PMID:20018760, PMID:19965641, PMID:22915648]. Downstream, CRLF2 engages a coordinated network of JAK/STAT5 and PI3K/AKT/mTOR signaling, interconnected such that JAK inhibition also abrogates PI3K/mTOR phosphorylation [PMID:22685175, PMID:26611474], together with co-activated CREB, MAPK/ERK, RAS (via CRKL), and IGF1R/FGFR1 signaling [PMID:29796158, PMID:32801162, PMID:34587248]. CRLF2 transcription is directly repressed by Ikaros (IKZF1), which binds the CRLF2 promoter and deposits H3K9me3 [PMID:27391346]. TSLP also signals through TSLPR-dependent PI3K/Akt to promote platelet activation and thrombus formation [PMID:25591759].","teleology":[{"year":2001,"claim":"Established the molecular identity of CRLF2 as a type I cytokine receptor and mapped it to the pseudoautosomal region, defining the structural framework for its receptor function.","evidence":"cDNA cloning, sequence analysis, and FISH mapping; expression profiling in dendritic cells and monocytes with LPS induction","pmids":["11474172","11237741"],"confidence":"Medium","gaps":["Ligand and dimerization partner not yet identified","Signaling output uncharacterized"]},{"year":2002,"claim":"Identified CRLF2/TSLPR as the heterodimeric partner of IL-7Ralpha that constitutes the functional TSLP receptor, defining its physiological signaling complex.","evidence":"Cloning, cross-species sequence alignment, and receptor reconstitution assays","pmids":["11891057"],"confidence":"Medium","gaps":["Intracellular signaling residues not mapped","Downstream pathways not defined"]},{"year":2009,"claim":"Demonstrated that CRLF2 rearrangement/overexpression drives leukemic transformation by activating JAK-STAT and conferring cytokine-independent growth, cooperating with JAK2 mutations and serving as the scaffold for mutant JAK2.","evidence":"Ba/F3 transformation assays, retroviral co-expression of P2RY8-CRLF2 and mutant JAK2, primary B-progenitor transduction, and IL-3-substitution screen with patient validation","pmids":["19838194","19641190","20018760"],"confidence":"High","gaps":["Mechanistic basis distinguishing ligand- vs mutation-driven signaling not resolved","Downstream effectors beyond STAT undefined"]},{"year":2009,"claim":"Identified the F232C gain-of-function mutation as an activating lesion driving constitutive receptor dimerization, revealing a JAK2-mutation-independent oncogenic mechanism.","evidence":"Site-directed mutagenesis with Ba/F3 growth and phospho-JAK2 readouts, replicated across patient samples","pmids":["20018760","19965641"],"confidence":"High","gaps":["Kinase mediating F232C signaling not pinpointed at this stage","Structural basis of dimerization not solved"]},{"year":2010,"claim":"Mapped the intracellular tyrosine requirements for TSLP signaling, showing redundancy between IL-7Ralpha and CRLF2 cytoplasmic tyrosines in proliferative signaling.","evidence":"Systematic mutagenesis of cytoplasmic tyrosines with Ba/F3 TSLP-dependent proliferation assays","pmids":["20144186"],"confidence":"Medium","gaps":["Identity of tyrosine-binding effectors not determined","Single-lab finding"]},{"year":2012,"claim":"Dissected three distinct CRLF2 oncogenic signaling modes (TSLP, F232C, mutant JAK2), showing shared dependence on box1/W286 but divergent tyrosine requirements, and demonstrated interconnection of JAK/STAT and PI3K/mTOR networks.","evidence":"Domain/residue mutagenesis with proliferation readout and quantitative phosphotyrosine analysis; phospho-flow of primary ALL with JAK inhibition","pmids":["22915648","22685175"],"confidence":"High","gaps":["Precise adaptor coupling box1 to JAK not defined","Crosstalk node linking JAK to PI3K not identified"]},{"year":2015,"claim":"Established species-specific TSLP-receptor interaction and extended TSLPR signaling beyond leukemia to platelet activation via PI3K/Akt.","evidence":"TSLP stimulation of PDX cells comparing human vs mouse ligand; TSLPR knockout mouse platelet and thrombosis assays","pmids":["26611474","25591759"],"confidence":"Medium","gaps":["Structural basis of species specificity unresolved","Platelet TSLPR complex composition not defined"]},{"year":2016,"claim":"Identified transcriptional control of CRLF2 by Ikaros, defining an epigenetic repression mechanism via H3K9me3 deposition at the CRLF2 promoter.","evidence":"ChIP, CK2 inhibitor treatment, siRNA knockdown, and H3K9me3 ChIP in ALL cells","pmids":["27391346"],"confidence":"Medium","gaps":["Cofactors of Ikaros-mediated repression not identified","Single-lab finding"]},{"year":2021,"claim":"Defined cooperating oncogenic and therapeutic vulnerabilities, including HMGN1 cooperation in transformation and rational JAK-degrading PROTAC design enabled by JAK2 crystal structures.","evidence":"Ba/F3 transformation with HMGN1 plus inducible CRISPR KO xenograft; JAK2-inhibitor crystal structures with PROTAC synthesis and xenograft testing","pmids":["34857887","34110416"],"confidence":"High","gaps":["Mechanism of HMGN1 cooperation not detailed","Resistance to PROTAC degradation not assessed"]},{"year":2022,"claim":"Genome-wide and mechanistic studies refined the essential signaling components downstream of CRLF2, showing STAT5/STAT3 dispensability but JAK/IL7RA/RAS-CRKL dependence, and characterized E2F-driven differentiation block.","evidence":"Genome-wide CRISPR dropout screen with CRKL depletion; Dp16 Down syndrome B-progenitor colony assays and gene expression profiling","pmids":["34587248","35306048"],"confidence":"Medium","gaps":["Role of RAS/CRKL relative to JAK signaling not fully delineated","Single-lab findings"]},{"year":2022,"claim":"Mapped the broader CRLF2 phosphotyrosine network and identified mechanisms of and routes to overcome therapeutic resistance.","evidence":"SILAC phosphotyrosine profiling identifying IGF1R/FGFR1 and Rap1; CyTOF mapping of JAK/STAT-PI3K-CREB network with SRC/ABL inhibition; high-dose TSLP receptor downregulation; BCL6/TP53 resistance axis with FX1","pmids":["32801162","29796158","36613920","36005560"],"confidence":"Medium","gaps":["Hierarchy among the many activated kinases unclear","Translational durability of combination strategies unestablished"]},{"year":null,"claim":"The structural basis of CRLF2/IL-7Ralpha heterodimer assembly and how distinct activating lesions reshape the receptor to couple to specific kinases and downstream effectors remains incompletely resolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the assembled CRLF2 receptor complex in the corpus","Direct adaptor coupling box1/W286 to JAK activation not defined","Mechanism integrating JAK/STAT, PI3K, RAS, and IGF1R/FGFR1 outputs unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,7,0,1]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[7,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[12]}],"complexes":["TSLP receptor (CRLF2/IL-7Ralpha heterodimer)"],"partners":["IL7R","JAK2","JAK1","CRKL","STAT5","IKZF1","HMGN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HC73","full_name":"Cytokine receptor-like factor 2","aliases":["Cytokine receptor-like 2","IL-XR","Thymic stromal lymphopoietin protein receptor","TSLP receptor"],"length_aa":371,"mass_kda":42.0,"function":"Receptor for thymic stromal lymphopoietin (TSLP). Forms a functional complex with TSLP and IL7R which is capable of stimulating cell proliferation through activation of STAT3 and STAT5. Also activates JAK2 (By similarity). Implicated in the development of the hematopoietic system","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9HC73/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRLF2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CRLF2","total_profiled":1310},"omim":[{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"607003","title":"THYMIC STROMAL LYMPHOPOIETIN; TSLP","url":"https://www.omim.org/entry/607003"},{"mim_id":"400023","title":"CYTOKINE RECEPTOR-LIKE FACTOR 2, Y-LINKED; CRLF2Y","url":"https://www.omim.org/entry/400023"},{"mim_id":"300525","title":"PYRIMIDINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 8; P2RY8","url":"https://www.omim.org/entry/300525"},{"mim_id":"300357","title":"CYTOKINE RECEPTOR-LIKE FACTOR 2; CRLF2","url":"https://www.omim.org/entry/300357"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":1.7},{"tissue":"gallbladder","ntpm":1.2},{"tissue":"lymphoid tissue","ntpm":1.4}],"url":"https://www.proteinatlas.org/search/CRLF2"},"hgnc":{"alias_symbol":["CRL2","TSLPR"],"prev_symbol":[]},"alphafold":{"accession":"Q9HC73","domains":[{"cath_id":"2.60.40.10","chopping":"29-116","consensus_level":"high","plddt":94.2113,"start":29,"end":116},{"cath_id":"2.60.40.10","chopping":"120-214","consensus_level":"high","plddt":95.902,"start":120,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HC73","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HC73-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HC73-F1-predicted_aligned_error_v6.png","plddt_mean":77.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRLF2","jax_strain_url":"https://www.jax.org/strain/search?query=CRLF2"},"sequence":{"accession":"Q9HC73","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HC73.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HC73/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HC73"}},"corpus_meta":[{"pmid":"19838194","id":"PMC_19838194","title":"Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19838194","citation_count":459,"is_preprint":false},{"pmid":"20139093","id":"PMC_20139093","title":"Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20139093","citation_count":444,"is_preprint":false},{"pmid":"19641190","id":"PMC_19641190","title":"Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19641190","citation_count":375,"is_preprint":false},{"pmid":"20018760","id":"PMC_20018760","title":"Functional screening identifies CRLF2 in precursor 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Clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/33890726","citation_count":6,"is_preprint":false},{"pmid":"20663412","id":"PMC_20663412","title":"Identifying the polymorphisms in the thymic stromal lymphopoietin receptor (TSLPR) and their association with asthma.","date":"2010","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/20663412","citation_count":6,"is_preprint":false},{"pmid":"29879498","id":"PMC_29879498","title":"Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29879498","citation_count":6,"is_preprint":false},{"pmid":"39461880","id":"PMC_39461880","title":"CRLF2-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy.","date":"2024","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39461880","citation_count":6,"is_preprint":false},{"pmid":"38698266","id":"PMC_38698266","title":"CRL2KLHDC3 and CRL1Fbxw7 cooperatively mediate c-Myc degradation.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38698266","citation_count":5,"is_preprint":false},{"pmid":"36613920","id":"PMC_36613920","title":"TSLP as a Potential Therapy in the Treatment of CRLF2 B Cell Acute Lymphoblastic Leukemia.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36613920","citation_count":5,"is_preprint":false},{"pmid":"34481852","id":"PMC_34481852","title":"A recombinant antibody fragment directed to the thymic stromal lymphopoietin receptor (CRLF2) efficiently targets pediatric Philadelphia chromosome-like acute lymphoblastic leukemia.","date":"2021","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/34481852","citation_count":5,"is_preprint":false},{"pmid":"39821119","id":"PMC_39821119","title":"TSLP and TSLPr Expression and Localization in the Airways of COPD and Non-COPD Patients.","date":"2025","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39821119","citation_count":4,"is_preprint":false},{"pmid":"30578688","id":"PMC_30578688","title":"CRLF2 expression associates with ICN1 stabilization in T-cell acute lymphoblastic leukemia.","date":"2019","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30578688","citation_count":4,"is_preprint":false},{"pmid":"33491417","id":"PMC_33491417","title":"Characterization of CRLF2 Expression in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.","date":"2021","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/33491417","citation_count":4,"is_preprint":false},{"pmid":"32801162","id":"PMC_32801162","title":"Targeting TSLP-Induced Tyrosine Kinase Signaling Pathways in CRLF2-Rearranged Ph-like ALL.","date":"2020","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/32801162","citation_count":4,"is_preprint":false},{"pmid":"35159975","id":"PMC_35159975","title":"Metal Allergy Mediates the Development of Oral Lichen Planus via TSLP-TSLPR Signaling.","date":"2022","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35159975","citation_count":4,"is_preprint":false},{"pmid":"38069558","id":"PMC_38069558","title":"An intrinsic network of polar interactions is responsible for binding of UL49.5 C-degron by the CRL2KLHDC3 ubiquitin ligase.","date":"2023","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/38069558","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54399,"output_tokens":5567,"usd":0.123351,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":27784,"output_tokens":8872,"usd":0.264367,"resynth_parse_fail":true,"stage2_stop_reason":"end_turn"},"total_usd":0.387718,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"CRLF2 rearrangement (P2RY8-CRLF2 fusion) co-operates with activating JAK2 mutations to cause constitutive JAK-STAT activation and cytokine-independent growth; expression of P2RY8-CRLF2 together with mutated Jak2 in Ba/F3 cells overexpressing IL-7Rα resulted in constitutive Jak-Stat activation and cytokine-independent proliferation.\",\n      \"method\": \"Ba/F3 cell transformation assay; retroviral co-expression of P2RY8-CRLF2 and mutant Jak2\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-based functional reconstitution replicated across multiple independent groups (PMID 19838194, 19641190, 19965641)\",\n      \"pmids\": [\"19838194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRLF2 overexpression activates the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation, indicating a causal role in lymphoid transformation.\",\n      \"method\": \"Retroviral transduction of primary B-cell progenitors with CRLF2; JAK-STAT phosphorylation assays; proliferation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional experiment in primary cells, replicated by multiple groups\",\n      \"pmids\": [\"19641190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRLF2 encodes a type I cytokine receptor subunit that, when overexpressed, can substitute for IL-3 signaling in a functional screen; CRLF2 acts as the key scaffold for mutant JAK2 signaling in B-ALL, since all 22 B-ALLs with mutant JAK2 overexpressed CRLF2.\",\n      \"method\": \"Functional mRNA screen for IL-3 signaling substitution; Ba/F3 cytokine-independent growth assay; phospho-JAK2 analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays in single study with broad patient sample validation\",\n      \"pmids\": [\"20018760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A gain-of-function CRLF2 F232C mutation promotes constitutive receptor dimerization and cytokine-independent growth in Ba/F3 cells; this differs mechanistically from WT CRLF2/mutant JAK2 signaling (which involves JAK2 phosphorylation) versus CRLF2 F232C (which does not involve JAK2 phosphorylation).\",\n      \"method\": \"Ba/F3 cytokine-independent growth assay; phospho-JAK2 Western blotting; site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with functional readout, replicated in patient samples across multiple groups\",\n      \"pmids\": [\"20018760\", \"19965641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRLF2 and mutated JAK2 cooperate in conferring cytokine-independent growth to BaF3 pro-B cells; the F232C mutation in CRLF2 was identified as an activating somatic mutation.\",\n      \"method\": \"Ba/F3 transformation assay; retroviral co-expression of CRLF2 variants and mutant JAK2\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional cell-based assay replicated across multiple independent studies\",\n      \"pmids\": [\"19965641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CRLF2 was identified as a type I cytokine receptor with an extracellular domain containing two fibronectin type III-like domains, four conserved cysteine residues, a WSXWS box-like motif, and an intracellular domain containing box 1 and box 2-like motifs; the gene is located in the pseudoautosomal region Xp22.3/Yp11.3.\",\n      \"method\": \"cDNA cloning from T-lymphocyte library; sequence analysis; FISH mapping\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cDNA cloning and FISH, replicated by independent group (PMID 11237741)\",\n      \"pmids\": [\"11474172\", \"11237741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CRLF2 (CRL2) is a type I transmembrane cytokine receptor preferentially expressed by dendritic cells and activated monocytes; its expression is upregulated by LPS stimulation of monocytes; the intracellular domain contains a box 1 motif and a conserved tyrosine potentially binding signal-transducing molecules.\",\n      \"method\": \"cDNA library screening; RT-PCR; Northern blot; LPS stimulation; Ba/F3 transfection with FLAG-tagged CRLF2; immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — expression characterization combined with transfection and immunoprecipitation; single lab\",\n      \"pmids\": [\"11237741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TSLPR (CRLF2) forms a heterodimeric complex with the IL-7 receptor alpha chain to form the functional receptor for TSLP; the WSXWX motif is conserved across mouse, rat, and human TSLPR; alternative splicing produces two functional receptor variants in mice.\",\n      \"method\": \"Cloning; sequence alignment; zooblot; alternative splice variant analysis; receptor reconstitution assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional receptor reconstitution and structural characterization, single study\",\n      \"pmids\": [\"11891057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TSLP-dependent cell proliferation requires at least one cytoplasmic tyrosine residue in either IL-7Rα or CRLF2; the single tyrosine residue in human CRLF2 alone is NOT required for TSLP-dependent proliferation; tyrosine residues in IL-7Rα and CRLF2 play redundant roles in TSLP-mediated growth signaling.\",\n      \"method\": \"Site-directed mutagenesis of IL-7Rα and CRLF2 cytoplasmic tyrosines; Ba/F3 TSLP-dependent proliferation assay\",\n      \"journal\": \"BMC immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"20144186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CRLF2 signaling through three distinct mechanisms (TSLP stimulation, CRLF2 F232C mutation, and CRLF2/mutant JAK2) differs at the level of intracellular tyrosines: CRLF2 F232C requires intracellular tyrosine Y368, while TSLP- or mutant JAK2-driven signaling does not; all three modes require the CRLF2 box1 domain and intracellular tryptophan W286.\",\n      \"method\": \"Domain mutation analysis; Ba/F3 proliferation assay; global quantitative phosphotyrosine analysis; Western blotting\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional readout plus quantitative phosphoproteomics, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22915648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CRLF2-rearranged ALL exhibits elevated basal pJAK2, pSTAT5, and pS6; TSLP stimulation of these leukemias induces robust JAK/STAT and PI3K/mTOR pathway signaling; JAK inhibition also abrogates PI3K/mTOR pathway phosphorylation, indicating interconnection between these signaling networks.\",\n      \"method\": \"Phospho-flow cytometry of primary ALL samples; TSLP stimulation assays; JAK inhibitor treatment with pathway readout\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — analysis of large numbers of primary patient samples with multiple pathway readouts, multiple orthogonal inhibitor experiments\",\n      \"pmids\": [\"22685175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSLP stimulates human CRLF2-overexpressing ALL via JAK/STAT5 and PI3K/AKT/mTOR pathways; mouse TSLP does NOT activate these downstream pathways in human CRLF2-rearranged ALL, demonstrating species-specific ligand–receptor interaction.\",\n      \"method\": \"TSLP stimulation of patient-derived xenograft samples; JAK/STAT5 and PI3K/AKT/mTOR phosphorylation assays; comparison of human vs. mouse TSLP\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct signaling assays in patient-derived cells, single lab, includes a functionally informative negative result\",\n      \"pmids\": [\"26611474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSLP stimulates platelet activation and thrombus formation via a TSLPR-dependent PI3K/Akt signaling pathway; TSLPR is expressed on murine platelets, and TSLPR-deficient platelets show defective aggregation, secretion, and in vivo thrombus formation.\",\n      \"method\": \"Western blotting; flow cytometry; TSLPR knockout mice; perfusion chambers; FeCl3 carotid artery thrombosis model; PI3K inhibitor assays\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype with defined signaling mechanism, single lab\",\n      \"pmids\": [\"25591759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ikaros (IKZF1-encoded protein) directly binds the CRLF2 promoter and represses CRLF2 transcription; CK2 inhibitor increases Ikaros binding to the CRLF2 promoter and suppresses CRLF2 expression in an Ikaros-dependent manner; this repression is associated with increased H3K9me3 histone modifications at the CRLF2 promoter.\",\n      \"method\": \"ChIP assay; CK2 inhibitor treatment; siRNA knockdown; H3K9me3 ChIP in ALL cell lines and primary cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional validation, multiple cell types, single lab\",\n      \"pmids\": [\"27391346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HMGN1 overexpression in combination with P2RY8-CRLF2 in Ba/F3 cells results in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development; HMGN1 knockout mitigates CRLF2-rearranged leukemia burden in vivo.\",\n      \"method\": \"Ba/F3 transformation assay; inducible CRISPR/Cas9 knockout xenograft model; in vivo engraftment studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell transformation assay combined with in vivo KO model, single lab\",\n      \"pmids\": [\"34857887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRLF2 overexpression in Dp16 (Down syndrome model) B-progenitor cells results in enhanced immature B-lymphoid colony development and reduced B-cell differentiation, associated with a gene expression signature of E2F signaling; PI3K/mTOR and pan-CDK inhibitors show cytotoxicity in CRLF2-rearranged B-ALL.\",\n      \"method\": \"Dp16 mouse model; colony assays; gene expression profiling; inhibitor cytotoxicity assays in cell lines and patient samples\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with defined cellular phenotype and gene expression pathway identification, single lab\",\n      \"pmids\": [\"35306048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRLF2-rearranged Ph-like ALL leukemia cells demonstrate relative glucocorticoid resistance; inhibition of MEK (trametinib) or Akt (MK2206), but NOT JAK inhibition (ruxolitinib), is sufficient to augment glucocorticoid sensitivity, indicating that MAPK/Akt rather than JAK-STAT signaling mediates GC resistance downstream of CRLF2.\",\n      \"method\": \"Patient-derived xenograft GC sensitivity assays; targeted inhibitor studies with MEK, Akt, and JAK inhibitors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PDX-based functional experiment with pathway dissection via specific inhibitors, single lab\",\n      \"pmids\": [\"31318944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JAK-directed PROTACs (proteolysis-targeting chimeras) degrade JAKs and potently kill CRLF2-rearranged ALL cell lines; solving crystal structures of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled rational PROTAC design; dual JAK/GSPT1-degrading PROTACs were most potent, with JAK2-degrading, GSPT1-sparing PROTACs also efficacious in kinase-driven xenografts.\",\n      \"method\": \"Crystal structure determination of JAK2-inhibitor complexes; PROTAC synthesis and testing; cell viability assays; xenograft models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with rational drug design, in vitro and in vivo validation, multiple PROTACs tested\",\n      \"pmids\": [\"34110416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Genome-wide CRISPR-Cas9 dropout screens showed that STAT5A, STAT5B, and STAT3 are largely dispensable for IgH-CRLF2-rearranged ALL cell survival, while CRLF2, IL7RA, JAK1/2, and RAS signaling regulators (particularly CRKL) are critical; CRKL depletion enhances ruxolitinib sensitivity in RAS wild-type cells.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 dropout screen; sgRNA fitness analysis; CRKL depletion experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide functional screen with specific mechanistic follow-up, single lab\",\n      \"pmids\": [\"34587248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"High-dose TSLP induced apoptosis and loss of CRLF2 receptor expression in CRLF2 B-ALL cell lines in vitro, and prevented engraftment/prolonged survival in patient-derived xenograft mice; mechanistically, high TSLP doses caused receptor downregulation and loss of downstream CRLF2 signaling.\",\n      \"method\": \"In vitro cell line apoptosis assay; patient-derived xenograft in vivo model; receptor surface expression by flow cytometry; signaling pathway Western blotting\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with mechanistic signaling readout, single lab\",\n      \"pmids\": [\"36613920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRLF2-rearranged leukemia treated with ruxolitinib upregulates BCL6, which suppresses TP53 and pro-apoptotic molecules (FAS, TNFRSF10B, BID, BAX, BAK, PUMA, NOXA), conferring resistance; BCL6 inhibition combined with ruxolitinib restores TP53 expression, enhances apoptosis, and prolongs survival in xenografted mice.\",\n      \"method\": \"Gene expression analysis post-ruxolitinib treatment; BCL6 inhibitor (FX1) experiments; Western blotting for TP53 and apoptotic markers; xenograft survival assay\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"36005560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In CRLF2-overexpressing B-ALL, a coordinated signaling network downstream of CRLF2 involves co-activation of JAK/STAT, PI3K, and CREB pathways; this network can be more effectively disrupted by SRC/ABL inhibition than by single-agent JAK or PI3K inhibition.\",\n      \"method\": \"Single-cell mass cytometry (CyTOF) on 15 primary patient samples; SRC/ABL inhibitor functional assays including in MRD cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell mass cytometry with inhibitor validation in primary samples, single lab\",\n      \"pmids\": [\"29796158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TSLP stimulation of CRLF2-rearranged Ph-like ALL cells activates JAK1, JAK2, STAT5, ERK1/2, IGF1R, and FGFR1 phosphotyrosine signaling, as well as the Rap1 signaling pathway; phosphotyrosine profiling identified IGF1R and FGFR1 as novel TSLP-activated kinases in this context.\",\n      \"method\": \"Phosphotyrosine (P-Tyr) profiling with SILAC; TSLP stimulation of CRLF2-rearranged cell lines; tyrosine kinase inhibitor synergy assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative phosphoproteomics with SILAC, single lab, two cell line models\",\n      \"pmids\": [\"32801162\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRLF2 (TSLPR) encodes a type I cytokine receptor subunit that heterodimerizes with IL-7Rα to form the TSLP receptor; overexpression or activating mutations (F232C causing constitutive dimerization; co-occurring JAK1/2 mutations) drive constitutive JAK/STAT and PI3K/mTOR signaling to promote cytokine-independent B-cell progenitor proliferation and leukemogenesis, with downstream pathway activation depending on the specific oncogenic mechanism (TSLP-ligand vs. F232C vs. mutant JAK2), and CRLF2 expression is transcriptionally repressed by Ikaros (IKZF1) via H3K9me3 deposition at its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CRLF2 (TSLPR) encodes a type I cytokine receptor subunit bearing two fibronectin type III-like domains, a WSXWS-like motif, and intracellular box1/box2 motifs that heterodimerizes with the IL-7 receptor alpha chain to form the functional receptor for TSLP [#5, #7]. Originally characterized as a receptor expressed by dendritic cells and activated monocytes whose surface levels rise upon LPS stimulation [#6], CRLF2 is best defined mechanistically as a driver of B-cell progenitor leukemogenesis: rearrangement (P2RY8-CRLF2) or overexpression activates the JAK-STAT pathway and confers cytokine-independent proliferation, cooperating with activating JAK2 mutations and acting as the obligate scaffold for mutant JAK2 signaling in B-ALL [#0, #1, #2]. An activating F232C mutation drives constitutive receptor dimerization and growth through a mechanism distinct from TSLP- or mutant-JAK2-driven signaling, with the three modes differing in their dependence on specific intracellular tyrosines (F232C requires Y368) while all require the box1 domain and intracellular tryptophan W286 [#3, #4, #9]. Downstream, CRLF2 engages a coordinated network of JAK/STAT5 and PI3K/AKT/mTOR signaling, interconnected such that JAK inhibition also abrogates PI3K/mTOR phosphorylation [#10, #11], together with co-activated CREB, MAPK/ERK, RAS (via CRKL), and IGF1R/FGFR1 signaling [#21, #22, #18]. CRLF2 transcription is directly repressed by Ikaros (IKZF1), which binds the CRLF2 promoter and deposits H3K9me3 [#13]. TSLP also signals through TSLPR-dependent PI3K/Akt to promote platelet activation and thrombus formation [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the molecular identity of CRLF2 as a type I cytokine receptor and mapped it to the pseudoautosomal region, defining the structural framework for its receptor function.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and FISH mapping; expression profiling in dendritic cells and monocytes with LPS induction\",\n      \"pmids\": [\"11474172\", \"11237741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand and dimerization partner not yet identified\", \"Signaling output uncharacterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified CRLF2/TSLPR as the heterodimeric partner of IL-7Ralpha that constitutes the functional TSLP receptor, defining its physiological signaling complex.\",\n      \"evidence\": \"Cloning, cross-species sequence alignment, and receptor reconstitution assays\",\n      \"pmids\": [\"11891057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling residues not mapped\", \"Downstream pathways not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that CRLF2 rearrangement/overexpression drives leukemic transformation by activating JAK-STAT and conferring cytokine-independent growth, cooperating with JAK2 mutations and serving as the scaffold for mutant JAK2.\",\n      \"evidence\": \"Ba/F3 transformation assays, retroviral co-expression of P2RY8-CRLF2 and mutant JAK2, primary B-progenitor transduction, and IL-3-substitution screen with patient validation\",\n      \"pmids\": [\"19838194\", \"19641190\", \"20018760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis distinguishing ligand- vs mutation-driven signaling not resolved\", \"Downstream effectors beyond STAT undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the F232C gain-of-function mutation as an activating lesion driving constitutive receptor dimerization, revealing a JAK2-mutation-independent oncogenic mechanism.\",\n      \"evidence\": \"Site-directed mutagenesis with Ba/F3 growth and phospho-JAK2 readouts, replicated across patient samples\",\n      \"pmids\": [\"20018760\", \"19965641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase mediating F232C signaling not pinpointed at this stage\", \"Structural basis of dimerization not solved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped the intracellular tyrosine requirements for TSLP signaling, showing redundancy between IL-7Ralpha and CRLF2 cytoplasmic tyrosines in proliferative signaling.\",\n      \"evidence\": \"Systematic mutagenesis of cytoplasmic tyrosines with Ba/F3 TSLP-dependent proliferation assays\",\n      \"pmids\": [\"20144186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of tyrosine-binding effectors not determined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Dissected three distinct CRLF2 oncogenic signaling modes (TSLP, F232C, mutant JAK2), showing shared dependence on box1/W286 but divergent tyrosine requirements, and demonstrated interconnection of JAK/STAT and PI3K/mTOR networks.\",\n      \"evidence\": \"Domain/residue mutagenesis with proliferation readout and quantitative phosphotyrosine analysis; phospho-flow of primary ALL with JAK inhibition\",\n      \"pmids\": [\"22915648\", \"22685175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise adaptor coupling box1 to JAK not defined\", \"Crosstalk node linking JAK to PI3K not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established species-specific TSLP-receptor interaction and extended TSLPR signaling beyond leukemia to platelet activation via PI3K/Akt.\",\n      \"evidence\": \"TSLP stimulation of PDX cells comparing human vs mouse ligand; TSLPR knockout mouse platelet and thrombosis assays\",\n      \"pmids\": [\"26611474\", \"25591759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of species specificity unresolved\", \"Platelet TSLPR complex composition not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified transcriptional control of CRLF2 by Ikaros, defining an epigenetic repression mechanism via H3K9me3 deposition at the CRLF2 promoter.\",\n      \"evidence\": \"ChIP, CK2 inhibitor treatment, siRNA knockdown, and H3K9me3 ChIP in ALL cells\",\n      \"pmids\": [\"27391346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactors of Ikaros-mediated repression not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined cooperating oncogenic and therapeutic vulnerabilities, including HMGN1 cooperation in transformation and rational JAK-degrading PROTAC design enabled by JAK2 crystal structures.\",\n      \"evidence\": \"Ba/F3 transformation with HMGN1 plus inducible CRISPR KO xenograft; JAK2-inhibitor crystal structures with PROTAC synthesis and xenograft testing\",\n      \"pmids\": [\"34857887\", \"34110416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of HMGN1 cooperation not detailed\", \"Resistance to PROTAC degradation not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genome-wide and mechanistic studies refined the essential signaling components downstream of CRLF2, showing STAT5/STAT3 dispensability but JAK/IL7RA/RAS-CRKL dependence, and characterized E2F-driven differentiation block.\",\n      \"evidence\": \"Genome-wide CRISPR dropout screen with CRKL depletion; Dp16 Down syndrome B-progenitor colony assays and gene expression profiling\",\n      \"pmids\": [\"34587248\", \"35306048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of RAS/CRKL relative to JAK signaling not fully delineated\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the broader CRLF2 phosphotyrosine network and identified mechanisms of and routes to overcome therapeutic resistance.\",\n      \"evidence\": \"SILAC phosphotyrosine profiling identifying IGF1R/FGFR1 and Rap1; CyTOF mapping of JAK/STAT-PI3K-CREB network with SRC/ABL inhibition; high-dose TSLP receptor downregulation; BCL6/TP53 resistance axis with FX1\",\n      \"pmids\": [\"32801162\", \"29796158\", \"36613920\", \"36005560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among the many activated kinases unclear\", \"Translational durability of combination strategies unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CRLF2/IL-7Ralpha heterodimer assembly and how distinct activating lesions reshape the receptor to couple to specific kinases and downstream effectors remains incompletely resolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the assembled CRLF2 receptor complex in the corpus\", \"Direct adaptor coupling box1/W286 to JAK activation not defined\", \"Mechanism integrating JAK/STAT, PI3K, RAS, and IGF1R/FGFR1 outputs unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 7, 0, 1]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"TSLP receptor (CRLF2/IL-7Ralpha heterodimer)\"\n    ],\n    \"partners\": [\n      \"IL7R\",\n      \"JAK2\",\n      \"JAK1\",\n      \"CRKL\",\n      \"STAT5\",\n      \"IKZF1\",\n      \"HMGN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}