{"gene":"PRR14L","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2018,"finding":"ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype, establishing a functional role for PRR14L in hematopoietic differentiation. RNA-Seq and cellular localization studies further suggested a role for PRR14L in cell division.","method":"shRNA knockdown in human CD34+ cells, in vitro hematopoietic differentiation assay, RNA-Seq, cellular localization studies","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype (skewed monocyte/neutrophil differentiation), supported by RNA-Seq and localization; single lab, moderate orthogonal methods","pmids":["30573780"],"is_preprint":false},{"year":2025,"finding":"Proximity labeling (TurboID) of PRR14L identified the PP2A-B56 phosphatase complex and the spindle assembly factor TACC3 as PRR14L-interacting proteins, defining PRR14L as a scaffold linking the PP2A-TACC3 axis. Loss of PRR14L prolongs spindle assembly checkpoint (SAC)-dependent mitotic arrest in response to microtubule depolymerization but leads to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors, placing PRR14L as a regulator of mitotic fidelity upstream of MPS1-dependent checkpoint signaling.","method":"TurboID proximity labeling, CRISPR/Cas9 loss-of-function screen (genome-wide, using MPS1 inhibitor NMS-P715), mitotic arrest and error assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling plus CRISPR loss-of-function with defined mitotic phenotype; single lab preprint, not yet peer-reviewed","pmids":["41279925"],"is_preprint":true}],"current_model":"PRR14L functions as a scaffold protein that links the PP2A-B56 phosphatase complex to the spindle assembly factor TACC3, regulating mitotic fidelity; its loss skews hematopoietic differentiation toward monocytes at the expense of neutrophils, and loss-of-function mutations are recurrently found biallelically in clonal hematopoiesis and myeloid neoplasms including CMML."},"narrative":{"teleology":[{"year":2018,"claim":"Whether PRR14L has a functional role in hematopoiesis was unknown; shRNA knockdown in CD34+ progenitors established that PRR14L loss shifts myeloid differentiation toward monocytes and away from neutrophils, linking it to a CMML-like phenotype and implicating it in cell division.","evidence":"shRNA knockdown in human CD34+ cells with in vitro differentiation assay, RNA-Seq, and cellular localization studies","pmids":["30573780"],"confidence":"Medium","gaps":["Mechanism by which PRR14L loss alters differentiation balance is undefined","No direct interacting partners identified at this stage","In vivo validation of the hematopoietic phenotype is lacking"]},{"year":2025,"claim":"The molecular mechanism of PRR14L in mitosis was unresolved; proximity labeling and genome-wide CRISPR screening identified PRR14L as a scaffold connecting PP2A-B56 to TACC3 and showed that its loss deregulates spindle assembly checkpoint dynamics, positioning PRR14L as a mitotic fidelity factor upstream of MPS1-dependent signaling.","evidence":"TurboID proximity labeling and genome-wide CRISPR/Cas9 loss-of-function screen with MPS1 inhibitor in human cell lines (preprint)","pmids":["41279925"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed or independently replicated","Direct biochemical reconstitution of the PRR14L–PP2A-B56–TACC3 ternary complex has not been performed","Whether the mitotic scaffolding function accounts for the hematopoietic differentiation phenotype is untested"]},{"year":null,"claim":"How PRR14L's mitotic scaffolding role mechanistically connects to its hematopoietic differentiation function, and whether its loss drives clonal hematopoiesis through mitotic error accumulation, remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo genetic model linking mitotic fidelity defects to myeloid skewing","Structural basis of PRR14L interaction with PP2A-B56 and TACC3 is unknown","No patient-derived mutation functional studies connecting specific PRR14L variants to disease phenotype"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":[],"partners":["PPP2R5A","PPP2R5C","PPP2R5D","TACC3"],"other_free_text":[]},"mechanistic_narrative":"PRR14L is a scaffold protein that bridges the PP2A-B56 phosphatase complex to the spindle assembly factor TACC3, thereby regulating mitotic fidelity; its loss prolongs spindle assembly checkpoint (SAC)-dependent mitotic arrest and sensitizes cells to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors [PMID:41279925]. In hematopoietic progenitors, PRR14L knockdown skews differentiation toward monocytes at the expense of neutrophils, recapitulating features of chronic myelomonocytic leukemia (CMML), and RNA-Seq analysis implicates PRR14L in cell division programs [PMID:30573780]."},"prefetch_data":{"uniprot":{"accession":"Q5THK1","full_name":"Protein PRR14L","aliases":["Proline rich 14-like protein"],"length_aa":2151,"mass_kda":237.3,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5THK1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRR14L","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ALDH16A1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HSPA4","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2},{"gene":"TNPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRR14L","total_profiled":1310},"omim":[{"mim_id":"621035","title":"PROLINE-RICH PROTEIN 14-LIKE PROTEIN; PRR14L","url":"https://www.omim.org/entry/621035"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRR14L"},"hgnc":{"alias_symbol":["MGC50372"],"prev_symbol":["C22orf30"]},"alphafold":{"accession":"Q5THK1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5THK1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5THK1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5THK1-F1-predicted_aligned_error_v6.png","plddt_mean":35.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRR14L","jax_strain_url":"https://www.jax.org/strain/search?query=PRR14L"},"sequence":{"accession":"Q5THK1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5THK1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5THK1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5THK1"}},"corpus_meta":[{"pmid":"30573780","id":"PMC_30573780","title":"PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia.","date":"2018","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/30573780","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37810911","id":"PMC_37810911","title":"Next-Generation Sequencing Analysis of 3 Uterine Adenosarcomas with Heterogeneously Differentiated Genomic Mutations.","date":"2023","source":"International journal of analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37810911","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41279925","id":"PMC_41279925","title":"The scaffold protein PRR14L links the PP2A-TACC3 axis to mitotic fidelity and sensitivity to MPS1 inhibition.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279925","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.11.14.25340228","title":"Tandem Repeat Polymorphisms Are Associated with Brain Structure: Results of Two Large Population-based Studies","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.25340228","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19156129","id":"PMC_19156129","title":"An integrated workflow for charting the human interaction proteome: insights into the PP2A system.","date":"2009","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/19156129","citation_count":223,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17207965","id":"PMC_17207965","title":"hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17207965","citation_count":222,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29117863","id":"PMC_29117863","title":"RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination.","date":"2017","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/29117863","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34349018","id":"PMC_34349018","title":"Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34349018","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29467282","id":"PMC_29467282","title":"Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function.","date":"2018","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/29467282","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24939585","id":"PMC_24939585","title":"Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24939585","citation_count":78,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26972000","id":"PMC_26972000","title":"Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26972000","citation_count":77,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19875381","id":"PMC_19875381","title":"A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein.","date":"2009","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/19875381","citation_count":76,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31586073","id":"PMC_31586073","title":"The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31586073","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24778252","id":"PMC_24778252","title":"TRIM65 regulates microRNA activity by ubiquitination of TNRC6.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24778252","citation_count":69,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28330616","id":"PMC_28330616","title":"Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.","date":"2017","source":"Cell systems","url":"https://pubmed.ncbi.nlm.nih.gov/28330616","citation_count":65,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36138187","id":"PMC_36138187","title":"NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.","date":"2022","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36138187","citation_count":46,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25476789","id":"PMC_25476789","title":"Proteomic analysis and identification of cellular interactors of the giant ubiquitin ligase HERC2.","date":"2014","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/25476789","citation_count":45,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30945288","id":"PMC_30945288","title":"Inflammation-dependent overexpression of c-Myc enhances CRL4DCAF4 E3 ligase activity and promotes ubiquitination of ST7 in colitis-associated cancer.","date":"2019","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30945288","citation_count":35,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34672954","id":"PMC_34672954","title":"An antibody-based proximity labeling map reveals mechanisms of SARS-CoV-2 inhibition of antiviral immunity.","date":"2021","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/34672954","citation_count":35,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15461802","id":"PMC_15461802","title":"A genome annotation-driven approach to cloning the human ORFeome.","date":"2004","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/15461802","citation_count":32,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35439318","id":"PMC_35439318","title":"A Whole-Genome CRISPR Screen Identifies AHR Loss as a Mechanism of Resistance to a PARP7 Inhibitor.","date":"2022","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/35439318","citation_count":24,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37827155","id":"PMC_37827155","title":"Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability.","date":"2023","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/37827155","citation_count":23,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33916271","id":"PMC_33916271","title":"N-Terminal Acetyltransferase Naa40p Whereabouts Put into N-Terminal Proteoform Perspective.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33916271","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35563538","id":"PMC_35563538","title":"Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35563538","citation_count":18,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3181,"output_tokens":733,"usd":0.010269},"stage2":{"model":"claude-opus-4-6","input_tokens":3914,"output_tokens":860,"usd":0.061605},"total_usd":0.174684,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":15645,"output_tokens":1524,"usd":0.034897},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4090,"output_tokens":993,"usd":0.067913}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"ShRNA knockdown of PRR14L in human CD34+ cells caused an increase in monocytes and decrease in neutrophils in vitro, suggesting PRR14L plays a role in myeloid differentiation; cellular localization studies further implicated PRR14L in cell division.\",\n      \"method\": \"ShRNA knockdown in human CD34+ cells followed by in vitro growth and differentiation assays; RNA-Seq; cellular localization studies\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and localization, but single lab and limited mechanistic pathway placement\",\n      \"pmids\": [\"30573780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Proximity labeling of PRR14L using TurboID identified the PP2A-B56 phosphatase complex and the spindle assembly factor TACC3 as PRR14L-interacting proteins, establishing PRR14L as a scaffold linking the PP2A-TACC3 axis to mitotic fidelity.\",\n      \"method\": \"TurboID proximity labeling mass spectrometry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling interactome in single study, not yet peer-reviewed\",\n      \"pmids\": [\"41279925\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of PRR14L prolongs spindle assembly checkpoint (SAC)-dependent mitotic arrest in response to microtubule depolymerization, but leads to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors, placing PRR14L as a regulator of mitotic fidelity downstream of or parallel to MPS1/TTK.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function screen with NMS-P715 (MPS1 inhibitor); functional follow-up with PRR14L KO cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CRISPR screen plus functional follow-up with defined mitotic phenotype, but preprint from single lab\",\n      \"pmids\": [\"41279925\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRR14L is a scaffold protein that interacts with the PP2A-B56 phosphatase complex and TACC3 to regulate mitotic fidelity; its loss disrupts spindle assembly checkpoint dynamics, and knockdown in hematopoietic progenitors skews differentiation toward monocytes at the expense of neutrophils, suggesting roles in both cell division and myeloid lineage determination.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n1. PMID:30573780 — KEEP: directly about PRR14L mutations, knockdown, and cellular function\n2. PMID:37810911 — KEEP: identifies BCORL1-PRR14L fusion in uterine adenosarcoma (mentions PRR14L)\n3. PMID:41279925 — KEEP: directly about PRR14L as scaffold protein in mitosis (preprint)\n4. bio_10.1101_2025.11.14.25340228 — EXCLUDE: GWAS/association study, no mechanistic finding about PRR14L protein\n5. PMID:12477932 — EXCLUDE: general cDNA sequencing resource\n6. PMID:26186194, 28514442, 33961781 — EXCLUDE: BioPlex interactome resources (PRR14L may appear but no specific mechanistic finding)\n7. PMID:26496610 — EXCLUDE: general interactome resource\n8. PMID:29507755 — EXCLUDE: about VIRMA/m6A methyltransferase\n9. PMID:14702039 — EXCLUDE: general cDNA sequencing\n10. PMID:35271311 — EXCLUDE: general proteome cartography resource\n11. PMID:16344560 — EXCLUDE: alternative promoters resource\n12. PMID:19156129 — EXCLUDE: PP2A system interactome, not PRR14L-specific\n13. PMID:17207965 — EXCLUDE: ORFeome resource\n14. PMID:29117863 — EXCLUDE: TRIM25, not PRR14L\n15. PMID:34349018 — EXCLUDE: general XL-MS interactome\n16. PMID:20379614 — EXCLUDE: smoking cessation GWAS\n17. PMID:29467282 — EXCLUDE: VCP substrates\n18. PMID:24939585 — EXCLUDE: hearing impairment GWAS\n19. PMID:26972000 — EXCLUDE: PHD3/FIH substrates\n20. PMID:19875381 — EXCLUDE: HSP90/CHORDC1\n21. PMID:31586073 — EXCLUDE: midbody interactome/PP1\n22. PMID:24778252 — EXCLUDE: TRIM65/TNRC6\n23. PMID:28330616 — EXCLUDE: phosphatase interactions\n24. PMID:36138187 — EXCLUDE: NUDT21/CD19\n25. PMID:25476789 — EXCLUDE: HERC2 ubiquitin ligase\n26. PMID:30945288 — EXCLUDE: CRL4DCAF4/ST7\n27. PMID:34672954 — EXCLUDE: SARS-CoV-2 proximity labeling\n28. PMID:15461802 — EXCLUDE: ORFeome cloning\n29. PMID:35439318 — EXCLUDE: PARP7 inhibitor screen\n30. PMID:37827155 — EXCLUDE: RPA/CAG repeat instability\n31. PMID:33916271 — EXCLUDE: Naa40p acetyltransferase\n32. PMID:35563538 — EXCLUDE: Cullin3 E3 ligase\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype, establishing a functional role for PRR14L in hematopoietic differentiation. RNA-Seq and cellular localization studies further suggested a role for PRR14L in cell division.\",\n      \"method\": \"shRNA knockdown in human CD34+ cells, in vitro hematopoietic differentiation assay, RNA-Seq, cellular localization studies\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype (skewed monocyte/neutrophil differentiation), supported by RNA-Seq and localization; single lab, moderate orthogonal methods\",\n      \"pmids\": [\"30573780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Proximity labeling (TurboID) of PRR14L identified the PP2A-B56 phosphatase complex and the spindle assembly factor TACC3 as PRR14L-interacting proteins, defining PRR14L as a scaffold linking the PP2A-TACC3 axis. Loss of PRR14L prolongs spindle assembly checkpoint (SAC)-dependent mitotic arrest in response to microtubule depolymerization but leads to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors, placing PRR14L as a regulator of mitotic fidelity upstream of MPS1-dependent checkpoint signaling.\",\n      \"method\": \"TurboID proximity labeling, CRISPR/Cas9 loss-of-function screen (genome-wide, using MPS1 inhibitor NMS-P715), mitotic arrest and error assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling plus CRISPR loss-of-function with defined mitotic phenotype; single lab preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41279925\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRR14L functions as a scaffold protein that links the PP2A-B56 phosphatase complex to the spindle assembly factor TACC3, regulating mitotic fidelity; its loss skews hematopoietic differentiation toward monocytes at the expense of neutrophils, and loss-of-function mutations are recurrently found biallelically in clonal hematopoiesis and myeloid neoplasms including CMML.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRR14L is a mitotic scaffold protein that interacts with the PP2A-B56 phosphatase complex and the spindle assembly factor TACC3, linking phosphatase activity to spindle assembly checkpoint (SAC) dynamics; its loss prolongs SAC-dependent mitotic arrest and causes catastrophic mitotic errors when the checkpoint is pharmacologically abrogated [PMID:41279925]. In human CD34+ hematopoietic progenitors, PRR14L knockdown skews myeloid differentiation toward monocytes at the expense of neutrophils, indicating an additional role in myeloid lineage determination [PMID:30573780].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"The first functional evidence for PRR14L established that it influences myeloid lineage choice, answering whether this uncharacterized gene has a role in hematopoiesis.\",\n      \"evidence\": \"shRNA knockdown in human CD34+ cells with in vitro differentiation assays and RNA-Seq\",\n      \"pmids\": [\"30573780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication\",\n        \"No molecular mechanism linking PRR14L to monocyte/neutrophil fate decision\",\n        \"Whether the differentiation phenotype is secondary to a cell-division defect was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proximity labeling and loss-of-function screening together defined PRR14L as a mitotic scaffold that connects PP2A-B56 and TACC3 to spindle assembly checkpoint fidelity, answering what molecular partners mediate its role in cell division.\",\n      \"evidence\": \"(preprint) TurboID proximity labeling mass spectrometry combined with genome-wide CRISPR screen using MPS1 inhibitor and functional validation in PRR14L knockout cells\",\n      \"pmids\": [\"41279925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed; interactions await reciprocal biochemical validation\",\n        \"Whether PRR14L directly bridges PP2A-B56 to TACC3 or interacts with each independently is unresolved\",\n        \"Structural basis for scaffold function is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the myeloid differentiation phenotype is mechanistically coupled to PRR14L's mitotic scaffold function or represents an independent pathway, and no in vivo loss-of-function model has been reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vivo animal model for PRR14L loss of function\",\n        \"Relationship between mitotic fidelity role and hematopoietic differentiation role is unexplored\",\n        \"No disease-causative mutations identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PPP2R5A\", \"TACC3\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PRR14L is a scaffold protein that bridges the PP2A-B56 phosphatase complex to the spindle assembly factor TACC3, thereby regulating mitotic fidelity; its loss prolongs spindle assembly checkpoint (SAC)-dependent mitotic arrest and sensitizes cells to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors [PMID:41279925]. In hematopoietic progenitors, PRR14L knockdown skews differentiation toward monocytes at the expense of neutrophils, recapitulating features of chronic myelomonocytic leukemia (CMML), and RNA-Seq analysis implicates PRR14L in cell division programs [PMID:30573780].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether PRR14L has a functional role in hematopoiesis was unknown; shRNA knockdown in CD34+ progenitors established that PRR14L loss shifts myeloid differentiation toward monocytes and away from neutrophils, linking it to a CMML-like phenotype and implicating it in cell division.\",\n      \"evidence\": \"shRNA knockdown in human CD34+ cells with in vitro differentiation assay, RNA-Seq, and cellular localization studies\",\n      \"pmids\": [\"30573780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which PRR14L loss alters differentiation balance is undefined\",\n        \"No direct interacting partners identified at this stage\",\n        \"In vivo validation of the hematopoietic phenotype is lacking\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The molecular mechanism of PRR14L in mitosis was unresolved; proximity labeling and genome-wide CRISPR screening identified PRR14L as a scaffold connecting PP2A-B56 to TACC3 and showed that its loss deregulates spindle assembly checkpoint dynamics, positioning PRR14L as a mitotic fidelity factor upstream of MPS1-dependent signaling.\",\n      \"evidence\": \"TurboID proximity labeling and genome-wide CRISPR/Cas9 loss-of-function screen with MPS1 inhibitor in human cell lines (preprint)\",\n      \"pmids\": [\"41279925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint; not yet peer-reviewed or independently replicated\",\n        \"Direct biochemical reconstitution of the PRR14L–PP2A-B56–TACC3 ternary complex has not been performed\",\n        \"Whether the mitotic scaffolding function accounts for the hematopoietic differentiation phenotype is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRR14L's mitotic scaffolding role mechanistically connects to its hematopoietic differentiation function, and whether its loss drives clonal hematopoiesis through mitotic error accumulation, remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vivo genetic model linking mitotic fidelity defects to myeloid skewing\",\n        \"Structural basis of PRR14L interaction with PP2A-B56 and TACC3 is unknown\",\n        \"No patient-derived mutation functional studies connecting specific PRR14L variants to disease phenotype\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PPP2R5A\", \"PPP2R5C\", \"PPP2R5D\", \"TACC3\"],\n    \"other_free_text\": []\n  }\n}\n```"}