{"gene":"IL3RA","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1993,"finding":"The IL3RA gene (encoding the IL-3 receptor alpha chain, CD123) was mapped to the X-Y pseudoautosomal region at bands Xp22.3 and Yp11.3 by Southern analysis of somatic cell hybrid panels, pulsed-field gel electrophoresis, and fluorescence chromosomal in situ hybridization. Pseudoautosomal inheritance was demonstrated by an EcoRI RFLP.","method":"Southern blotting, pulsed-field gel electrophoresis, fluorescence in situ hybridization, somatic cell hybrid analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal direct mapping methods in a single study with genetic validation","pmids":["8213838"],"is_preprint":false},{"year":2016,"finding":"Expression of IL3RA (CD123) on AML cells is transcriptionally regulated by the H3K9/H3K36 demethylases Jmjd2/Kdm4 through removal of H3K9me3 from the Il3ra gene promoter. Conditional triple-knockout of Jmjd2a/b/c reduced IL3ra expression, and ectopic re-expression of Il3ra in knockout cells rescued AML cell survival, establishing Il3ra as a critical downstream effector of Jmjd2/Kdm4 in leukemia.","method":"Conditional knockout mouse genetics, chromatin immunoprecipitation (H3K9me3 at Il3ra promoter), rescue by ectopic Il3ra expression, in vitro and in vivo AML survival assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic epistasis with rescue experiment plus ChIP showing H3K9me3 removal at the IL3RA promoter, multiple orthogonal methods in one study","pmids":["27257215"],"is_preprint":false},{"year":2019,"finding":"Resistance to tagraxofusp (IL-3 fused to diphtheria toxin targeting CD123) was mechanistically linked to deficiencies in the diphthamide biosynthesis pathway (specifically reduced DPH1 expression via CpG methylation), which impairs the drug's ability to ADP-ribosylate its cellular targets. DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. Resistance was not associated with loss of CD123 expression.","method":"Drug resistance characterization in patient samples and cell lines, ADP-ribosylation assay, bisulfite/methylation analysis of DPH1 promoter, azacitidine rescue experiments, patient-derived xenograft models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic dissection using multiple orthogonal methods (ADP-ribosylation assay, methylation analysis, rescue by demethylating agent, in vivo PDX validation) in a single rigorous study","pmids":["31437130"],"is_preprint":false},{"year":2017,"finding":"The anti-CD123 antibody CSL362 demonstrated that CD123 is expressed on 100% of primary AML samples including CD34+CD38-CD123+ leukemic stem cells, and that CSL362 potently induces antibody-dependent cell cytotoxicity (ADCC) of AML blasts including LSCs by NK cells. NK cells from AML patients in remission had comparable ADCC activity to healthy donor NK cells.","method":"Flow cytometry, in vitro ADCC assays with NK cells, primary AML patient samples","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ADCC assays with primary patient material, single lab, two orthogonal approaches (expression profiling + functional killing)","pmids":["28574487"],"is_preprint":false},{"year":2014,"finding":"The anti-CD123 monoclonal antibody CSL360 neutralizes IL-3 signaling: doses ≥3.0 mg/kg in AML patients resulted in complete saturation and down-regulation of CD123 on blasts and abolition of ex vivo proliferative responsiveness to IL-3, indicating that CD123 blockade inhibits IL-3 receptor signaling in vivo.","method":"Phase 1 clinical study with pharmacodynamic assessment: flow cytometry for CD123 surface saturation and ex vivo IL-3 proliferation assay","journal":"Leukemia & lymphoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pharmacodynamic measurement of receptor occupancy and functional IL-3 signaling blockade in patients, single study","pmids":["25248882"],"is_preprint":false},{"year":2007,"finding":"Single-chain Fv immunotoxins targeting CD123 (26292(Fv)-PE38 and variants) bind CD123 with Kd of 3.5 nM and mediate specific cytotoxicity of CD123-expressing leukemia cell lines. Mutating the C-terminal REDLK to KDEL in 26292(Fv)-PE38 increased cytotoxic activity approximately 5-fold, demonstrating that optimizing ER-retrieval sequences enhances immunotoxin potency. Cytotoxicity was strictly dependent on CD123 expression level.","method":"In vitro cytotoxicity assays, binding affinity measurements, site-directed mutagenesis of C-terminal retention sequence","journal":"Journal of immunotherapy","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution with mutagenesis, single lab","pmids":["17667524"],"is_preprint":false},{"year":2017,"finding":"SGN-CD123A, a CD123-targeted antibody-drug conjugate using a pyrrolobenzodiazepine dimer linker, mechanistically induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells following receptor-mediated internalization.","method":"In vitro cytotoxicity assays, DNA damage response pathway analysis, cell-cycle analysis, apoptosis assays, in vivo xenograft models","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic assays in single lab, single study","pmids":["29142066"],"is_preprint":false},{"year":2017,"finding":"Anti-CD123 antibody-modified niosomes demonstrated receptor-mediated endocytic internalization by CD123+ AML cells, with uptake efficiency dependent on antibody (ligand) density. Preincubation with free anti-CD123 antibody competitively blocked niosome uptake, confirming the CD123-mediated endocytic mechanism.","method":"Flow cytometry, competitive inhibition assay, uptake mechanism analysis in AML cell lines","journal":"Drug delivery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method category (competitive inhibition), no structural or mutagenesis validation","pmids":["28574300"],"is_preprint":false},{"year":2019,"finding":"SL-101, an anti-CD123 single-chain Fv fused to Pseudomonas exotoxin A, mediates cytotoxicity via rapid internalization of the antibody conjugate, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL-3-induced p-STAT5 and p-AKT signaling pathways in CD123+ AML cells.","method":"Internalization assay, protein synthesis inhibition assay, apoptosis assay, phospho-flow cytometry for p-STAT5 and p-AKT, colony-forming assay, patient-derived xenograft","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic assays (internalization, protein synthesis, signaling pathway blockade, apoptosis) in single lab","pmids":["28096272"],"is_preprint":false},{"year":2019,"finding":"Two anti-CD123 antibodies (H9 and CSL362) recognize different epitopes on the N-terminal domain of CD123, as revealed by crystallography and SPOT peptide analysis. Both antibodies in IgG1 format mediate selective killing of leukemic cells in ADCC assays; when reformatted as bispecific BiTE reagents fused to anti-CD3, CSL362-BiTE exhibited ~10-fold higher potency than H9-BiTE in killing AML blasts by autologous T cells.","method":"X-ray crystallography, SPOT peptide epitope mapping, in vitro ADCC assays, BiTE-mediated T-cell killing assays with primary AML patient blasts","journal":"Leukemia research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of epitope binding plus functional validation by ADCC and BiTE killing assays in one study","pmids":["31326578"],"is_preprint":false},{"year":2023,"finding":"Expression of CD64 (high-affinity Fc receptor) on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro, identifying a mechanism by which AML cells evade CD123-targeted antibody therapy.","method":"In vitro ADCC assay with primary AML blasts stratified by CD64 expression","journal":"Nature biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ADCC assay demonstrating mechanistic resistance, single lab, primary patient samples","pmids":["36635380"],"is_preprint":false},{"year":2019,"finding":"CD123 surface expression on endothelial cells is upregulated when co-cultured with activated CART123 cells, and this upregulation is mediated by IFN-γ and TNF-α released by CAR T cells. Neutralization of IFN-γ and TNF-α reversed CD123 upregulation on endothelial cells. CD123 is also expressed on CART123 cells themselves and is upregulated upon T-cell activation, potentially causing fratricide.","method":"Flow cytometry, co-culture model, ELISA for cytokines, neutralizing antibody experiments","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vitro co-culture with cytokine neutralization, limited mechanistic depth","pmids":["31417286"],"is_preprint":false},{"year":2018,"finding":"IMGN632 (anti-CD123 antibody conjugated to a DNA mono-alkylating IGN payload) demonstrated potent cytotoxicity against AML cell lines and primary patient samples independent of multidrug resistance status. Mechanistically, it was >40-fold less cytotoxic to normal myeloid progenitors than a DNA crosslinking IGN-ADC (X-ADC) using the same antibody, establishing that the mono-alkylating payload confers the therapeutic window.","method":"In vitro cytotoxicity assays in AML cell lines, primary AML samples, normal bone marrow progenitors; in vivo AML xenograft models; comparative ADC payload analysis","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparative payload mechanism study with primary patient material and in vivo validation, single lab","pmids":["29661755"],"is_preprint":false},{"year":2016,"finding":"CD123 expression is dependent on Jmjd2/Kdm4-mediated H3K9me3 demethylation at the IL3RA gene promoter. Loss of Jmjd2a/b/c in AML cells increases H3K9me3 at the IL3ra promoter and reduces IL3ra transcript levels, while ectopic IL3ra expression rescues the AML cell survival defect caused by Jmjd2/Kdm4 knockout.","method":"ChIP for H3K9me3 at IL3ra promoter, RT-qPCR, conditional knockout, ectopic expression rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP demonstrating direct epigenetic regulation at the IL3RA locus plus genetic epistasis rescue, multiple methods in one rigorous study","pmids":["27257215"],"is_preprint":false},{"year":2023,"finding":"Epitope engineering of CD123 on hematopoietic stem and progenitor cells (HSPCs) shields them from CD123-targeted CAR T-cell cytotoxicity while preserving HSPC function. CD123-deficient HSPCs displayed a competitive disadvantage, indicating that CD123 is functionally required in normal HSPCs but that epitope modification (not complete deletion) maintains function while evading immunotherapy.","method":"Genome editing (base editors/prime editors) of CD123 epitope in HSPCs, CAR T-cell cytotoxicity assays, transplantation into humanized mice, differentiation and engraftment assessment","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (editing, functional assays, in vivo transplantation), direct functional consequence of CD123 modification established","pmids":["37773046"],"is_preprint":false},{"year":2024,"finding":"Prime editing of the CD123 epitope in HSPCs (increasing editing efficiency from 5.9% to 78.9%) renders cells resistant to anti-CD123 CAR-T lysis while retaining normal differentiation and function. In humanized mice, epitope-modified HSPCs engraft and endow myeloid lineages with selective resistance to CD123-targeted CAR-T immunotherapy.","method":"Base editing and prime editing, CAR-T cytotoxicity assays, differentiation assays, humanized mouse transplantation model","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — precision genome editing with functional in vitro and in vivo validation, multiple orthogonal methods, single rigorous study","pmids":["39353428"],"is_preprint":false}],"current_model":"IL3RA (CD123), the alpha subunit of the interleukin-3 receptor, is a cell-surface receptor whose transcription is epigenetically regulated by Jmjd2/Kdm4 demethylases through H3K9me3 removal at its promoter; upon ligand (IL-3) binding it transduces signals through STAT5 and AKT pathways; it is internalized upon antibody or conjugate binding, enabling delivery of cytotoxic payloads (immunotoxins, ADCs) that kill leukemic cells via DNA damage, protein synthesis inhibition, and apoptosis; CD64 expression on AML blasts can block anti-CD123 ADCC; and IFN-γ/TNF-α can upregulate CD123 on endothelial cells, contributing to on-target off-tumor toxicity of CD123-directed therapies."},"narrative":{"mechanistic_narrative":"IL3RA (CD123) is the cell-surface alpha subunit of the interleukin-3 receptor that transduces IL-3 signals through STAT5 and AKT to support myeloid and leukemic cell survival [PMID:28096272]. Its surface expression is set transcriptionally by Jmjd2/Kdm4 H3K9/H3K36 demethylases, which remove repressive H3K9me3 from the IL3RA promoter; loss of Jmjd2a/b/c raises promoter H3K9me3 and lowers IL3RA transcription, and ectopic IL3RA rescues the survival defect of demethylase-deficient AML cells, establishing IL3RA as a critical downstream effector of this epigenetic axis [PMID:27257215]. CD123 is expressed on essentially all primary AML samples, including CD34+CD38- leukemic stem cells, making it a dominant target for immunotherapy [PMID:28574487]. Antibodies against its N-terminal domain neutralize IL-3 signaling and drive selective killing of leukemic blasts via NK-cell ADCC and, when reformatted as anti-CD3 bispecifics, via autologous T cells [PMID:25248882, PMID:31326578]. Following antibody or ligand engagement CD123 undergoes receptor-mediated internalization, enabling delivery of cytotoxic payloads — immunotoxins, Pseudomonas-exotoxin and diphtheria-toxin fusions, and antibody-drug conjugates — that kill cells through protein-synthesis inhibition, DNA damage, and apoptosis [PMID:17667524, PMID:29142066, PMID:28096272]. Resistance to CD123-directed therapy arises not from loss of receptor but from downstream determinants such as silencing of the diphthamide-biosynthesis gene DPH1 (reversible by azacitidine) and from CD64 expression on blasts that blocks ADCC [PMID:31437130, PMID:36635380]. CD123 is functionally required in normal hematopoietic stem/progenitor cells, and epitope engineering of the receptor shields these cells from CD123-targeted CAR-T cytotoxicity while preserving their function [PMID:37773046, PMID:39353428].","teleology":[{"year":1993,"claim":"Establishing the chromosomal location of IL3RA defined the gene as a pseudoautosomal locus, providing the genetic foundation for studying its regulation and inheritance.","evidence":"Southern blotting, PFGE, FISH, and somatic cell hybrid mapping with an EcoRI RFLP","pmids":["8213838"],"confidence":"High","gaps":["Does not address receptor function or signaling","No link to disease at this stage"]},{"year":2016,"claim":"Identifying Jmjd2/Kdm4-mediated H3K9me3 removal at the IL3RA promoter answered how CD123 expression is set in leukemia and placed IL3RA as a survival-critical effector downstream of an epigenetic axis.","evidence":"Conditional Jmjd2a/b/c knockout, ChIP for H3K9me3 at the Il3ra promoter, and ectopic Il3ra rescue in AML survival assays","pmids":["27257215"],"confidence":"High","gaps":["Mechanism is defined in mouse AML models","Does not establish what downstream signaling IL3RA drives to support survival"]},{"year":2007,"claim":"Single-chain Fv immunotoxins showed CD123 could deliver cytotoxic cargo into leukemia cells, and optimizing the ER-retrieval sequence enhanced potency, validating CD123 as a payload-delivery receptor.","evidence":"In vitro cytotoxicity and binding assays with site-directed mutagenesis of the C-terminal retention sequence (REDLK to KDEL)","pmids":["17667524"],"confidence":"Medium","gaps":["Tested in cell lines, not primary patient material in this study","No in vivo validation"]},{"year":2014,"claim":"Demonstrating that an anti-CD123 antibody saturates and downregulates surface CD123 and abolishes IL-3 proliferative responses confirmed that CD123 blockade inhibits IL-3 receptor signaling in patients.","evidence":"Phase 1 pharmacodynamics: flow cytometry for receptor saturation and ex vivo IL-3 proliferation assay","pmids":["25248882"],"confidence":"Medium","gaps":["Does not detail the intracellular signaling cascade","Clinical efficacy not established by pharmacodynamics alone"]},{"year":2017,"claim":"CD123 expression on 100% of AML samples including leukemic stem cells, coupled with NK-mediated ADCC, established CD123 as a target reaching the LSC compartment.","evidence":"Flow cytometry expression profiling and in vitro NK-cell ADCC with primary AML samples (CSL362)","pmids":["28574487"],"confidence":"Medium","gaps":["Single-lab functional assays","Does not address off-tumor expression or resistance"]},{"year":2017,"claim":"Mechanistic dissection of internalizing CD123 conjugates clarified how delivered payloads kill cells — via DNA damage response, cell-cycle arrest, and apoptosis after receptor-mediated internalization.","evidence":"In vitro cytotoxicity, DNA damage response and cell-cycle analysis, apoptosis assays, and xenografts (SGN-CD123A); competitive endocytosis assays (niosomes)","pmids":["29142066","28574300"],"confidence":"Medium","gaps":["Niosome internalization evidence rests on a single competitive-inhibition method without structural/mutagenesis validation","Internalization kinetics and trafficking route not fully resolved"]},{"year":2019,"claim":"Combining crystallography with functional reformatting showed that distinct N-terminal epitopes can be exploited, and that BiTE format and epitope choice tune the potency of T-cell-mediated AML killing.","evidence":"X-ray crystallography, SPOT peptide epitope mapping, ADCC and anti-CD3 BiTE killing assays with primary AML blasts","pmids":["31326578"],"confidence":"High","gaps":["Structural basis for the potency difference between epitopes not fully explained","In vivo BiTE efficacy not established here"]},{"year":2019,"claim":"Mechanistic studies of an scFv-Pseudomonas exotoxin fusion linked CD123 engagement to rapid internalization, protein-synthesis inhibition, apoptosis, and blockade of IL-3-induced p-STAT5 and p-AKT, defining the receptor's signaling outputs.","evidence":"Internalization, protein-synthesis inhibition, phospho-flow for p-STAT5/p-AKT, apoptosis, colony-forming and PDX assays (SL-101)","pmids":["28096272"],"confidence":"Medium","gaps":["Signaling readouts measured as drug effects rather than primary receptor biochemistry","Single-lab study"]},{"year":2019,"claim":"Identifying that DPH1 silencing — not CD123 loss — drives tagraxofusp resistance reframed therapeutic failure as a payload-pathway problem reversible by demethylating agents.","evidence":"ADP-ribosylation assays, DPH1 promoter methylation analysis, azacitidine rescue, and PDX models from patient samples","pmids":["31437130"],"confidence":"High","gaps":["Specific to diphthamide-dependent toxin payloads","Does not address resistance to non-toxin CD123 therapies"]},{"year":2018,"claim":"Comparative payload analysis established that a mono-alkylating IGN payload, not the antibody, confers the therapeutic window against normal myeloid progenitors.","evidence":"Comparative in vitro cytotoxicity in AML cells, primary samples, and normal progenitors, plus xenografts (IMGN632 vs crosslinking X-ADC)","pmids":["29661755"],"confidence":"Medium","gaps":["Therapeutic window inferred from in vitro/xenograft comparisons","Clinical resistance mechanisms not addressed"]},{"year":2023,"claim":"Two findings defined limits to CD123 immunotherapy: CD64 on blasts blocks ADCC as a tumor-intrinsic escape mechanism, and CD123 upregulation on endothelial cells by CAR-T-derived IFN-γ/TNF-α explains on-target off-tumor toxicity.","evidence":"ADCC assays stratified by CD64 expression; co-culture with cytokine ELISA and neutralizing antibodies","pmids":["36635380","31417286"],"confidence":"Medium","gaps":["Endothelial upregulation evidence is a single-lab in vitro co-culture with limited mechanistic depth (Low confidence)","CD64-mediated resistance shown in vitro only"]},{"year":2024,"claim":"Epitope engineering of CD123 in normal HSPCs demonstrated the receptor is functionally required for HSPC fitness yet can be modified to evade CAR-T while preserving differentiation, enabling selective protection of healthy hematopoiesis.","evidence":"Base and prime editing of the CD123 epitope, CAR-T cytotoxicity, differentiation assays, and humanized mouse transplantation","pmids":["37773046","39353428"],"confidence":"High","gaps":["Precise function of CD123 in normal HSPCs not molecularly defined","Long-term safety of edited grafts not established"]},{"year":null,"claim":"The primary biochemistry of CD123 signaling — its direct interaction with the IL-3 receptor beta chain, downstream effector recruitment, and the molecular basis of its requirement in normal HSPCs — remains uncharacterized in this corpus.","evidence":"No timeline discovery reconstitutes IL3RA receptor complex assembly or maps its native signaling biochemistry","pmids":[],"confidence":"Low","gaps":["No reconstitution of the IL-3 receptor signaling complex","Molecular role of CD123 in normal HSPC fitness undefined","STAT5/AKT activation inferred mainly from drug-blockade experiments"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,8]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[5,7,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,10]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26951","full_name":"Interleukin-3 receptor subunit alpha","aliases":[],"length_aa":378,"mass_kda":43.3,"function":"Cell surface receptor for IL3 expressed on hematopoietic progenitor cells, monocytes and B-lymphocytes that controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells (PubMed:10527461). Ligand stimulation rapidly induces hetrodimerization with IL3RB, phosphorylation and enzyme activity of effector proteins such as JAK2 and PI3K that play a role in signaling cell proliferation and differentiation. Activation of JAK2 leads to STAT5-mediated transcriptional program (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P26951/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL3RA","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":74,"dependency_fraction":0.013513513513513514},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL3RA","total_profiled":1310},"omim":[{"mim_id":"620254","title":"RING FINGER PROTEIN, TRANSMEMBRANE 2; RNFT2","url":"https://www.omim.org/entry/620254"},{"mim_id":"614641","title":"LYSOSOME-ASSOCIATED MEMBRANE PROTEIN 5; LAMP5","url":"https://www.omim.org/entry/614641"},{"mim_id":"613936","title":"TRANSMEMBRANE PROTEIN 102; TMEM102","url":"https://www.omim.org/entry/613936"},{"mim_id":"606677","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER C; CLEC4C","url":"https://www.omim.org/entry/606677"},{"mim_id":"602069","title":"NEUROPILIN 1; NRP1","url":"https://www.omim.org/entry/602069"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IL3RA"},"hgnc":{"alias_symbol":["CD123"],"prev_symbol":[]},"alphafold":{"accession":"P26951","domains":[{"cath_id":"2.60.40.3850","chopping":"28-97","consensus_level":"high","plddt":93.3333,"start":28,"end":97},{"cath_id":"2.60.40.10","chopping":"109-205","consensus_level":"high","plddt":94.8352,"start":109,"end":205},{"cath_id":"2.60.40.10","chopping":"213-293","consensus_level":"high","plddt":94.4864,"start":213,"end":293}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26951","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26951-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26951-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL3RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL3RA"},"sequence":{"accession":"P26951","fasta_url":"https://rest.uniprot.org/uniprotkb/P26951.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26951/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26951"}},"corpus_meta":[{"pmid":"27571406","id":"PMC_27571406","title":"Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies.","date":"2016","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/27571406","citation_count":485,"is_preprint":false},{"pmid":"24927407","id":"PMC_24927407","title":"Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia.","date":"2014","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/24927407","citation_count":285,"is_preprint":false},{"pmid":"11698285","id":"PMC_11698285","title":"Reduced blood CD123+ (lymphoid) and CD11c+ (myeloid) dendritic cell numbers in primary HIV-1 infection.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11698285","citation_count":261,"is_preprint":false},{"pmid":"11726317","id":"PMC_11726317","title":"Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic 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Pseudoautosomal inheritance was demonstrated by an EcoRI RFLP.\",\n      \"method\": \"Southern blotting, pulsed-field gel electrophoresis, fluorescence in situ hybridization, somatic cell hybrid analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal direct mapping methods in a single study with genetic validation\",\n      \"pmids\": [\"8213838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Expression of IL3RA (CD123) on AML cells is transcriptionally regulated by the H3K9/H3K36 demethylases Jmjd2/Kdm4 through removal of H3K9me3 from the Il3ra gene promoter. Conditional triple-knockout of Jmjd2a/b/c reduced IL3ra expression, and ectopic re-expression of Il3ra in knockout cells rescued AML cell survival, establishing Il3ra as a critical downstream effector of Jmjd2/Kdm4 in leukemia.\",\n      \"method\": \"Conditional knockout mouse genetics, chromatin immunoprecipitation (H3K9me3 at Il3ra promoter), rescue by ectopic Il3ra expression, in vitro and in vivo AML survival assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic epistasis with rescue experiment plus ChIP showing H3K9me3 removal at the IL3RA promoter, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27257215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Resistance to tagraxofusp (IL-3 fused to diphtheria toxin targeting CD123) was mechanistically linked to deficiencies in the diphthamide biosynthesis pathway (specifically reduced DPH1 expression via CpG methylation), which impairs the drug's ability to ADP-ribosylate its cellular targets. DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. Resistance was not associated with loss of CD123 expression.\",\n      \"method\": \"Drug resistance characterization in patient samples and cell lines, ADP-ribosylation assay, bisulfite/methylation analysis of DPH1 promoter, azacitidine rescue experiments, patient-derived xenograft models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic dissection using multiple orthogonal methods (ADP-ribosylation assay, methylation analysis, rescue by demethylating agent, in vivo PDX validation) in a single rigorous study\",\n      \"pmids\": [\"31437130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The anti-CD123 antibody CSL362 demonstrated that CD123 is expressed on 100% of primary AML samples including CD34+CD38-CD123+ leukemic stem cells, and that CSL362 potently induces antibody-dependent cell cytotoxicity (ADCC) of AML blasts including LSCs by NK cells. NK cells from AML patients in remission had comparable ADCC activity to healthy donor NK cells.\",\n      \"method\": \"Flow cytometry, in vitro ADCC assays with NK cells, primary AML patient samples\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ADCC assays with primary patient material, single lab, two orthogonal approaches (expression profiling + functional killing)\",\n      \"pmids\": [\"28574487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The anti-CD123 monoclonal antibody CSL360 neutralizes IL-3 signaling: doses ≥3.0 mg/kg in AML patients resulted in complete saturation and down-regulation of CD123 on blasts and abolition of ex vivo proliferative responsiveness to IL-3, indicating that CD123 blockade inhibits IL-3 receptor signaling in vivo.\",\n      \"method\": \"Phase 1 clinical study with pharmacodynamic assessment: flow cytometry for CD123 surface saturation and ex vivo IL-3 proliferation assay\",\n      \"journal\": \"Leukemia & lymphoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pharmacodynamic measurement of receptor occupancy and functional IL-3 signaling blockade in patients, single study\",\n      \"pmids\": [\"25248882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Single-chain Fv immunotoxins targeting CD123 (26292(Fv)-PE38 and variants) bind CD123 with Kd of 3.5 nM and mediate specific cytotoxicity of CD123-expressing leukemia cell lines. Mutating the C-terminal REDLK to KDEL in 26292(Fv)-PE38 increased cytotoxic activity approximately 5-fold, demonstrating that optimizing ER-retrieval sequences enhances immunotoxin potency. Cytotoxicity was strictly dependent on CD123 expression level.\",\n      \"method\": \"In vitro cytotoxicity assays, binding affinity measurements, site-directed mutagenesis of C-terminal retention sequence\",\n      \"journal\": \"Journal of immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution with mutagenesis, single lab\",\n      \"pmids\": [\"17667524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SGN-CD123A, a CD123-targeted antibody-drug conjugate using a pyrrolobenzodiazepine dimer linker, mechanistically induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells following receptor-mediated internalization.\",\n      \"method\": \"In vitro cytotoxicity assays, DNA damage response pathway analysis, cell-cycle analysis, apoptosis assays, in vivo xenograft models\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic assays in single lab, single study\",\n      \"pmids\": [\"29142066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Anti-CD123 antibody-modified niosomes demonstrated receptor-mediated endocytic internalization by CD123+ AML cells, with uptake efficiency dependent on antibody (ligand) density. Preincubation with free anti-CD123 antibody competitively blocked niosome uptake, confirming the CD123-mediated endocytic mechanism.\",\n      \"method\": \"Flow cytometry, competitive inhibition assay, uptake mechanism analysis in AML cell lines\",\n      \"journal\": \"Drug delivery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method category (competitive inhibition), no structural or mutagenesis validation\",\n      \"pmids\": [\"28574300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SL-101, an anti-CD123 single-chain Fv fused to Pseudomonas exotoxin A, mediates cytotoxicity via rapid internalization of the antibody conjugate, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL-3-induced p-STAT5 and p-AKT signaling pathways in CD123+ AML cells.\",\n      \"method\": \"Internalization assay, protein synthesis inhibition assay, apoptosis assay, phospho-flow cytometry for p-STAT5 and p-AKT, colony-forming assay, patient-derived xenograft\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic assays (internalization, protein synthesis, signaling pathway blockade, apoptosis) in single lab\",\n      \"pmids\": [\"28096272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Two anti-CD123 antibodies (H9 and CSL362) recognize different epitopes on the N-terminal domain of CD123, as revealed by crystallography and SPOT peptide analysis. Both antibodies in IgG1 format mediate selective killing of leukemic cells in ADCC assays; when reformatted as bispecific BiTE reagents fused to anti-CD3, CSL362-BiTE exhibited ~10-fold higher potency than H9-BiTE in killing AML blasts by autologous T cells.\",\n      \"method\": \"X-ray crystallography, SPOT peptide epitope mapping, in vitro ADCC assays, BiTE-mediated T-cell killing assays with primary AML patient blasts\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of epitope binding plus functional validation by ADCC and BiTE killing assays in one study\",\n      \"pmids\": [\"31326578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Expression of CD64 (high-affinity Fc receptor) on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro, identifying a mechanism by which AML cells evade CD123-targeted antibody therapy.\",\n      \"method\": \"In vitro ADCC assay with primary AML blasts stratified by CD64 expression\",\n      \"journal\": \"Nature biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ADCC assay demonstrating mechanistic resistance, single lab, primary patient samples\",\n      \"pmids\": [\"36635380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD123 surface expression on endothelial cells is upregulated when co-cultured with activated CART123 cells, and this upregulation is mediated by IFN-γ and TNF-α released by CAR T cells. Neutralization of IFN-γ and TNF-α reversed CD123 upregulation on endothelial cells. CD123 is also expressed on CART123 cells themselves and is upregulated upon T-cell activation, potentially causing fratricide.\",\n      \"method\": \"Flow cytometry, co-culture model, ELISA for cytokines, neutralizing antibody experiments\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vitro co-culture with cytokine neutralization, limited mechanistic depth\",\n      \"pmids\": [\"31417286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IMGN632 (anti-CD123 antibody conjugated to a DNA mono-alkylating IGN payload) demonstrated potent cytotoxicity against AML cell lines and primary patient samples independent of multidrug resistance status. Mechanistically, it was >40-fold less cytotoxic to normal myeloid progenitors than a DNA crosslinking IGN-ADC (X-ADC) using the same antibody, establishing that the mono-alkylating payload confers the therapeutic window.\",\n      \"method\": \"In vitro cytotoxicity assays in AML cell lines, primary AML samples, normal bone marrow progenitors; in vivo AML xenograft models; comparative ADC payload analysis\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparative payload mechanism study with primary patient material and in vivo validation, single lab\",\n      \"pmids\": [\"29661755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD123 expression is dependent on Jmjd2/Kdm4-mediated H3K9me3 demethylation at the IL3RA gene promoter. Loss of Jmjd2a/b/c in AML cells increases H3K9me3 at the IL3ra promoter and reduces IL3ra transcript levels, while ectopic IL3ra expression rescues the AML cell survival defect caused by Jmjd2/Kdm4 knockout.\",\n      \"method\": \"ChIP for H3K9me3 at IL3ra promoter, RT-qPCR, conditional knockout, ectopic expression rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP demonstrating direct epigenetic regulation at the IL3RA locus plus genetic epistasis rescue, multiple methods in one rigorous study\",\n      \"pmids\": [\"27257215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Epitope engineering of CD123 on hematopoietic stem and progenitor cells (HSPCs) shields them from CD123-targeted CAR T-cell cytotoxicity while preserving HSPC function. CD123-deficient HSPCs displayed a competitive disadvantage, indicating that CD123 is functionally required in normal HSPCs but that epitope modification (not complete deletion) maintains function while evading immunotherapy.\",\n      \"method\": \"Genome editing (base editors/prime editors) of CD123 epitope in HSPCs, CAR T-cell cytotoxicity assays, transplantation into humanized mice, differentiation and engraftment assessment\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (editing, functional assays, in vivo transplantation), direct functional consequence of CD123 modification established\",\n      \"pmids\": [\"37773046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Prime editing of the CD123 epitope in HSPCs (increasing editing efficiency from 5.9% to 78.9%) renders cells resistant to anti-CD123 CAR-T lysis while retaining normal differentiation and function. In humanized mice, epitope-modified HSPCs engraft and endow myeloid lineages with selective resistance to CD123-targeted CAR-T immunotherapy.\",\n      \"method\": \"Base editing and prime editing, CAR-T cytotoxicity assays, differentiation assays, humanized mouse transplantation model\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — precision genome editing with functional in vitro and in vivo validation, multiple orthogonal methods, single rigorous study\",\n      \"pmids\": [\"39353428\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL3RA (CD123), the alpha subunit of the interleukin-3 receptor, is a cell-surface receptor whose transcription is epigenetically regulated by Jmjd2/Kdm4 demethylases through H3K9me3 removal at its promoter; upon ligand (IL-3) binding it transduces signals through STAT5 and AKT pathways; it is internalized upon antibody or conjugate binding, enabling delivery of cytotoxic payloads (immunotoxins, ADCs) that kill leukemic cells via DNA damage, protein synthesis inhibition, and apoptosis; CD64 expression on AML blasts can block anti-CD123 ADCC; and IFN-γ/TNF-α can upregulate CD123 on endothelial cells, contributing to on-target off-tumor toxicity of CD123-directed therapies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL3RA (CD123) is the cell-surface alpha subunit of the interleukin-3 receptor that transduces IL-3 signals through STAT5 and AKT to support myeloid and leukemic cell survival [#8]. Its surface expression is set transcriptionally by Jmjd2/Kdm4 H3K9/H3K36 demethylases, which remove repressive H3K9me3 from the IL3RA promoter; loss of Jmjd2a/b/c raises promoter H3K9me3 and lowers IL3RA transcription, and ectopic IL3RA rescues the survival defect of demethylase-deficient AML cells, establishing IL3RA as a critical downstream effector of this epigenetic axis [#1, #13]. CD123 is expressed on essentially all primary AML samples, including CD34+CD38- leukemic stem cells, making it a dominant target for immunotherapy [#3]. Antibodies against its N-terminal domain neutralize IL-3 signaling and drive selective killing of leukemic blasts via NK-cell ADCC and, when reformatted as anti-CD3 bispecifics, via autologous T cells [#4, #9]. Following antibody or ligand engagement CD123 undergoes receptor-mediated internalization, enabling delivery of cytotoxic payloads — immunotoxins, Pseudomonas-exotoxin and diphtheria-toxin fusions, and antibody-drug conjugates — that kill cells through protein-synthesis inhibition, DNA damage, and apoptosis [#5, #6, #8]. Resistance to CD123-directed therapy arises not from loss of receptor but from downstream determinants such as silencing of the diphthamide-biosynthesis gene DPH1 (reversible by azacitidine) and from CD64 expression on blasts that blocks ADCC [#2, #10]. CD123 is functionally required in normal hematopoietic stem/progenitor cells, and epitope engineering of the receptor shields these cells from CD123-targeted CAR-T cytotoxicity while preserving their function [#14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the chromosomal location of IL3RA defined the gene as a pseudoautosomal locus, providing the genetic foundation for studying its regulation and inheritance.\",\n      \"evidence\": \"Southern blotting, PFGE, FISH, and somatic cell hybrid mapping with an EcoRI RFLP\",\n      \"pmids\": [\"8213838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address receptor function or signaling\", \"No link to disease at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying Jmjd2/Kdm4-mediated H3K9me3 removal at the IL3RA promoter answered how CD123 expression is set in leukemia and placed IL3RA as a survival-critical effector downstream of an epigenetic axis.\",\n      \"evidence\": \"Conditional Jmjd2a/b/c knockout, ChIP for H3K9me3 at the Il3ra promoter, and ectopic Il3ra rescue in AML survival assays\",\n      \"pmids\": [\"27257215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism is defined in mouse AML models\", \"Does not establish what downstream signaling IL3RA drives to support survival\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Single-chain Fv immunotoxins showed CD123 could deliver cytotoxic cargo into leukemia cells, and optimizing the ER-retrieval sequence enhanced potency, validating CD123 as a payload-delivery receptor.\",\n      \"evidence\": \"In vitro cytotoxicity and binding assays with site-directed mutagenesis of the C-terminal retention sequence (REDLK to KDEL)\",\n      \"pmids\": [\"17667524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tested in cell lines, not primary patient material in this study\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that an anti-CD123 antibody saturates and downregulates surface CD123 and abolishes IL-3 proliferative responses confirmed that CD123 blockade inhibits IL-3 receptor signaling in patients.\",\n      \"evidence\": \"Phase 1 pharmacodynamics: flow cytometry for receptor saturation and ex vivo IL-3 proliferation assay\",\n      \"pmids\": [\"25248882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not detail the intracellular signaling cascade\", \"Clinical efficacy not established by pharmacodynamics alone\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CD123 expression on 100% of AML samples including leukemic stem cells, coupled with NK-mediated ADCC, established CD123 as a target reaching the LSC compartment.\",\n      \"evidence\": \"Flow cytometry expression profiling and in vitro NK-cell ADCC with primary AML samples (CSL362)\",\n      \"pmids\": [\"28574487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional assays\", \"Does not address off-tumor expression or resistance\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mechanistic dissection of internalizing CD123 conjugates clarified how delivered payloads kill cells — via DNA damage response, cell-cycle arrest, and apoptosis after receptor-mediated internalization.\",\n      \"evidence\": \"In vitro cytotoxicity, DNA damage response and cell-cycle analysis, apoptosis assays, and xenografts (SGN-CD123A); competitive endocytosis assays (niosomes)\",\n      \"pmids\": [\"29142066\", \"28574300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Niosome internalization evidence rests on a single competitive-inhibition method without structural/mutagenesis validation\", \"Internalization kinetics and trafficking route not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Combining crystallography with functional reformatting showed that distinct N-terminal epitopes can be exploited, and that BiTE format and epitope choice tune the potency of T-cell-mediated AML killing.\",\n      \"evidence\": \"X-ray crystallography, SPOT peptide epitope mapping, ADCC and anti-CD3 BiTE killing assays with primary AML blasts\",\n      \"pmids\": [\"31326578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the potency difference between epitopes not fully explained\", \"In vivo BiTE efficacy not established here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistic studies of an scFv-Pseudomonas exotoxin fusion linked CD123 engagement to rapid internalization, protein-synthesis inhibition, apoptosis, and blockade of IL-3-induced p-STAT5 and p-AKT, defining the receptor's signaling outputs.\",\n      \"evidence\": \"Internalization, protein-synthesis inhibition, phospho-flow for p-STAT5/p-AKT, apoptosis, colony-forming and PDX assays (SL-101)\",\n      \"pmids\": [\"28096272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling readouts measured as drug effects rather than primary receptor biochemistry\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying that DPH1 silencing — not CD123 loss — drives tagraxofusp resistance reframed therapeutic failure as a payload-pathway problem reversible by demethylating agents.\",\n      \"evidence\": \"ADP-ribosylation assays, DPH1 promoter methylation analysis, azacitidine rescue, and PDX models from patient samples\",\n      \"pmids\": [\"31437130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific to diphthamide-dependent toxin payloads\", \"Does not address resistance to non-toxin CD123 therapies\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Comparative payload analysis established that a mono-alkylating IGN payload, not the antibody, confers the therapeutic window against normal myeloid progenitors.\",\n      \"evidence\": \"Comparative in vitro cytotoxicity in AML cells, primary samples, and normal progenitors, plus xenografts (IMGN632 vs crosslinking X-ADC)\",\n      \"pmids\": [\"29661755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Therapeutic window inferred from in vitro/xenograft comparisons\", \"Clinical resistance mechanisms not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two findings defined limits to CD123 immunotherapy: CD64 on blasts blocks ADCC as a tumor-intrinsic escape mechanism, and CD123 upregulation on endothelial cells by CAR-T-derived IFN-γ/TNF-α explains on-target off-tumor toxicity.\",\n      \"evidence\": \"ADCC assays stratified by CD64 expression; co-culture with cytokine ELISA and neutralizing antibodies\",\n      \"pmids\": [\"36635380\", \"31417286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endothelial upregulation evidence is a single-lab in vitro co-culture with limited mechanistic depth (Low confidence)\", \"CD64-mediated resistance shown in vitro only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Epitope engineering of CD123 in normal HSPCs demonstrated the receptor is functionally required for HSPC fitness yet can be modified to evade CAR-T while preserving differentiation, enabling selective protection of healthy hematopoiesis.\",\n      \"evidence\": \"Base and prime editing of the CD123 epitope, CAR-T cytotoxicity, differentiation assays, and humanized mouse transplantation\",\n      \"pmids\": [\"37773046\", \"39353428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise function of CD123 in normal HSPCs not molecularly defined\", \"Long-term safety of edited grafts not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The primary biochemistry of CD123 signaling — its direct interaction with the IL-3 receptor beta chain, downstream effector recruitment, and the molecular basis of its requirement in normal HSPCs — remains uncharacterized in this corpus.\",\n      \"evidence\": \"No timeline discovery reconstitutes IL3RA receptor complex assembly or maps its native signaling biochemistry\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstitution of the IL-3 receptor signaling complex\", \"Molecular role of CD123 in normal HSPC fitness undefined\", \"STAT5/AKT activation inferred mainly from drug-blockade experiments\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [5, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}