{"gene":"MYCL","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1985,"finding":"L-myc (MYCL) was identified as a third myc-related gene, amplified and expressed in human small cell lung cancer (SCLC), mapping to human chromosome 1p32, distinct from c-myc and N-myc loci.","method":"Southern blot hybridization, gene mapping, Northern blot","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — foundational discovery with multiple orthogonal methods, >663 citations, widely replicated","pmids":["2997622"],"is_preprint":false},{"year":1987,"finding":"Human L-myc gene has a three-exon organization similar to c-myc and N-myc, encodes a 364 amino acid protein retaining five of seven conserved Myc homology regions, and can cooperate with mutant Ha-ras to transform rat embryo fibroblasts (cotransformation assay).","method":"Nucleotide sequencing, cotransformation assay in rat embryo fibroblasts","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — direct transformation assay with structural characterization, >126 citations","pmids":["3322939"],"is_preprint":false},{"year":1988,"finding":"L-myc gene generates multiple mRNA species from a single gene by alternative splicing of introns 1 and 2 and use of alternative polyadenylation signals; some transcripts encode a truncated protein with a novel carboxy-terminal end.","method":"Northern blot, cDNA sequencing, mRNA structure analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — detailed molecular characterization, >115 citations","pmids":["2827002"],"is_preprint":false},{"year":1988,"finding":"L-myc cooperates with activated ras to transform primary rat embryo fibroblasts, but with only 1–10% of the efficiency of c-myc; L-myc/ras transformants are tumorigenic in nude mice.","method":"Cotransformation assay with activated ras in rat embryo fibroblasts, nude mouse tumorigenicity assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — direct functional assay replicated across labs","pmids":["2457153"],"is_preprint":false},{"year":1988,"finding":"L-myc proteins p60 and p66 (molecular masses 60 and 66 kDa) are phosphorylated nuclear proteins localized to the nuclear matrix fraction; both arise from the 3.9 kb mRNA; the short-lived proteins have differential stability based on the mRNA isoform.","method":"Immunoprecipitation, subcellular fractionation, in vitro translation, Western blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — nuclear localization by fractionation with protein characterization, >45 citations","pmids":["3054516"],"is_preprint":false},{"year":1989,"finding":"L-myc protein phosphorylation is rapidly increased by phorbol ester (TPA) treatment or serum, correlating with protein kinase C activation; three polypeptides of 60–66 kDa are differentially phosphorylated forms of a common precursor (alkaline phosphatase converts them to a single ~59 kDa band).","method":"Immunoprecipitation with [35S]methionine and [32P]orthophosphate labeling, alkaline phosphatase treatment, phorbol ester stimulation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assay with multiple orthogonal methods demonstrating PTM","pmids":["2540955"],"is_preprint":false},{"year":1990,"finding":"Eµ-L-myc transgenic mice show preferential L-myc expression in T cells, thymic hyperplasia, and predisposition to T-cell lymphomas; the L-myc transgene can substitute for c- or N-myc in generating lymphoid neoplasms without detectable endogenous myc expression.","method":"Transgenic mouse model, FACS, histopathology, Northern blot","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic model with direct phenotypic readout","pmids":["2120050"],"is_preprint":false},{"year":1991,"finding":"Two SCLC cell lines express chimeric RLF-L-myc fusion proteins arising from intrachromosomal rearrangements that place the regulatory region and first exon of the novel gene RLF upstream of L-myc, representing an activation mechanism for the L-myc proto-oncogene.","method":"cDNA cloning, Northern blot, Southern blot, immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — molecular characterization of fusion protein across two independent cell lines","pmids":["1851085"],"is_preprint":false},{"year":1991,"finding":"RLF and L-myc genes are physically linked on chromosome 1p32 within <800 kb; their fusion results from intrachromosomal rearrangements producing identical chimeric proteins in independent SCLC cell lines.","method":"Somatic cell hybrid mapping, pulsed-field gel electrophoresis, Southern blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — physical mapping with functional context, >29 citations","pmids":["1649386"],"is_preprint":false},{"year":1991,"finding":"L-myc translation initiates from both an AUG codon in exon 2 and an unusual non-AUG (CUG) site in intron 1; the CUG-initiated protein (p65) also possesses transforming activity in rat embryo cells.","method":"In vitro translation, transfection/transformation assay in rat embryo cells, immunoprecipitation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical + functional transformation assay","pmids":["1849244"],"is_preprint":false},{"year":1992,"finding":"The N-terminal transcriptional activation domain of L-Myc activates transcription when fused to the GAL4 DNA-binding domain, but at only ~5% of c-Myc activity; chimera experiments show the activation domain potency determines cotransforming efficiency of L-Myc vs c-Myc.","method":"GAL4 fusion transcription activation assays, cotransformation assay in rat embryo fibroblasts, L-Myc/c-Myc chimeras","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted transcription assay with domain-swap mutagenesis","pmids":["1620120"],"is_preprint":false},{"year":1992,"finding":"PKC activation by TPA induces phosphorylation of L-myc at N-terminal serine residues 38 and 42; these serines can be phosphorylated in vitro by GSK-3β; mutating them to alanine abolishes heterogeneous electrophoretic migration and TPA-induced hyperphosphorylation.","method":"In vitro mutagenesis, in vitro kinase assay with GSK-3β, phorbol ester stimulation, phosphoamino acid analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus site-directed mutagenesis, identifies specific PTM sites and writer","pmids":["1312697"],"is_preprint":false},{"year":1992,"finding":"Forced L-myc expression in lens fiber cells causes severely disorganized fiber cell compartment and decreased late-stage differentiation marker (MIP26), demonstrating L-myc affects differentiation processes directly rather than through deregulated growth control; in contrast, c-myc inhibits cell cycle exit but not differentiation.","method":"αA-crystallin promoter transgenic mice, histology, molecular differentiation markers, BrdU proliferation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic approach with specific molecular readouts, contrasts L-myc vs c-myc","pmids":["7882978"],"is_preprint":false},{"year":1993,"finding":"L-Myc, like c-Myc, heterodimerizes with purified Max protein to bind the core DNA sequence CACGTG; Max expression augments L-Myc cotransforming activity; the bHLH-Zip domain of L-Myc interacts equivalently to c-Myc with Max.","method":"PCR-based binding site selection, pulldown/heterodimerization assay with bacterially synthesized proteins, cotransfection with Max expression vector","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay with purified proteins plus functional transformation data","pmids":["1620120","8455937"],"is_preprint":false},{"year":1993,"finding":"N- and L-Myc bind preferentially to CACGTG motifs and form heterodimeric DNA-binding complexes with Max; all three domains (BR, HLH, LZ) are required for DNA binding, while dimerization requires HLH and LZ.","method":"PCR-based binding site selection, mutational analysis of BR/HLH/LZ domains","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay with mutagenesis","pmids":["8455937"],"is_preprint":false},{"year":1995,"finding":"The RLF gene encodes a 1914 amino acid zinc finger protein with 16 zinc finger motifs related to the Zn-15 transcription factor; the RLF-L-myc fusions do not include zinc fingers, and transforming ability of RLF-L-myc is indistinguishable from normal L-myc, indicating rearrangement deregulates L-myc expression rather than creating a new oncogene.","method":"cDNA sequencing, transformation assay comparison","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — molecular characterization with functional comparison","pmids":["8545128"],"is_preprint":false},{"year":1996,"finding":"L-Myc is expressed in developing kidney, lung, and brain (proliferative and differentiative zones) in mouse; homozygous L-myc null mice are viable and reproductively competent with no detectable morphological abnormalities or compensatory changes in c- or N-myc, demonstrating L-Myc is dispensable for gross embryonic development.","method":"RNA in situ hybridization, gene targeting (knockout), histological analysis, BrdU proliferation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean knockout with comprehensive phenotypic analysis, >94 citations","pmids":["8657155"],"is_preprint":false},{"year":1998,"finding":"c-, N-, and L-myc oncoproteins all accelerate apoptosis in IL-3-dependent 32D cells after IL-3 withdrawal; however, unlike c-myc which sensitizes cells to cytotoxic drugs, N-myc and L-myc overexpression produce resistance to cytotoxic agents, identifying distinct apoptotic pathways regulated by each family member.","method":"Stable transfection in 32D hematopoietic cells, IL-3 withdrawal assay, cytotoxic drug treatment, apoptosis quantification","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/OE with defined cellular phenotype comparing family members","pmids":["9751117"],"is_preprint":false},{"year":2003,"finding":"CCL6 chemokine is a direct positive transcriptional target of L-Myc in 32D myeloid cells; L-Myc binds the CCL6 promoter as shown by chromatin immunoprecipitation; CCL6 coexpression with c-Myc abrogates IL-3 dependence and produces a leukemogenic phenotype.","method":"Chromatin immunoprecipitation (ChIP), reporter assays, stable transfection, tumorigenicity assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct promoter binding with functional consequence","pmids":["12782599"],"is_preprint":false},{"year":2004,"finding":"The 5' UTR of L-myc contains an IRES (internal ribosome entry segment) that accounts for all translation initiation from the L-myc mRNA; the ribosome entry window is upstream of the start codon, utilizing a 'land and scan' mechanism; a secondary structure model including a pseudoknot near the 5' end was derived.","method":"Bicistronic reporter assays, deletion mapping, RNA secondary structure modeling","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — direct functional assay with mutational mapping of IRES element","pmids":["14730027"],"is_preprint":false},{"year":2011,"finding":"A SNP (rs3134615) in the 3'-UTR of MYCL1 alters the binding site for hsa-miR-1827; the rs3134615 G>T change results in altered regulation of MYCL1 expression as shown by reporter gene assays.","method":"Reporter gene assay (3'-UTR luciferase), case-control analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay demonstrates functional miRNA-binding site, single lab","pmids":["21676885"],"is_preprint":false},{"year":2014,"finding":"Mycl1 is selectively expressed in dendritic cells (DCs) under IRF8 transcriptional control; expression transitions from c-Myc in progenitors to L-Myc in mature DCs; Mycl1-deficient mice have reduced migratory CD103+ conventional DCs and impaired in vivo T-cell priming during Listeria and VSV infection.","method":"Mycl1(gfp) reporter knock-in mice, flow cytometry, infection models (Listeria monocytogenes, VSV), immunofluorescence","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific functional phenotype (T-cell priming) in vivo, multiple infections, >64 citations","pmids":["24509714"],"is_preprint":false},{"year":2016,"finding":"L-Myc promotes pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis in neuroendocrine preneoplastic cells; deletion of Mycl in two genetically engineered SCLC mouse models (Rb/p53-deleted) strongly suppresses tumor formation; RNA polymerase I inhibition mimics this effect.","method":"Conditional Mycl knockout in SCLC mouse models, RNA-seq, pre-rRNA synthesis assay, RNA Pol I inhibitor treatment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — two independent genetic mouse models, multiple functional readouts, mechanistic link to rRNA synthesis","pmids":["27298335"],"is_preprint":false},{"year":2017,"finding":"Merkel cell polyomavirus Small T antigen (ST) binds specifically to MYCL and recruits it to the 15-component EP400 histone acetyltransferase/chromatin remodeling complex; the ST-MYCL-EP400 complex binds gene promoters and activates their expression; MYCL and EP400 are required for MCC cell viability and cooperate with ST in cellular transformation and iPSC generation.","method":"Large-scale immunoprecipitation with mass spectrometry, reciprocal Co-IP for MAX and EP400, ChIP-seq, RNA-seq, genome-wide CRISPR-Cas9 screen, transformation assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP confirmed by MS, ChIP-seq, RNA-seq, and CRISPR screen, multiple orthogonal methods in one study","pmids":["29028833"],"is_preprint":false},{"year":2020,"finding":"MYCL and MXD1 regulate a reciprocal transcriptional program during cDC1 maturation; Mycl-deficient immature cDC1s show reduced expression of genes regulating core biosynthetic processes; Mxd1-deficient mature cDC1s fail to suppress the MYCL-dependent transcriptional signature.","method":"Mycl-deficient and Mxd1-/- mice, RNA-seq, flow cytometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO of both reciprocal factors with transcriptomic readout, single lab","pmids":["32071205"],"is_preprint":false},{"year":2021,"finding":"IRF8 (in cooperation with PU.1 at EICEs within Mycl enhancers) drives the transition from c-Myc to L-Myc during DC specification; high IRF8 levels are required for this transition in cDC1s and pDCs; IRF8 also contributes to MYC repression; MYCL is most highly expressed in DCs that have exited the cell cycle.","method":"Reporter mice for MYC, MYCL, Geminin, CDT1; IRF8 mutant mice; Irf8 enhancer deletion (+41kb); flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic mouse models with reporters, identifies specific transcription factor and enhancer element","pmids":["34958351"],"is_preprint":false},{"year":2021,"finding":"RLF-MYCL fusion accelerates SCLC tumor formation, proliferation, and metastatic dissemination in a CRISPR/Cas9-engineered mouse model; gene expression similarities confirmed between mouse and human RLF-MYCL SCLC, establishing RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC.","method":"CRISPR/Cas9 somatic genome editing to generate Rlf-Mycl mouse model, RNA-seq, tumor growth and metastasis quantification","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 — genetically engineered mouse model with direct causal evidence of fusion in oncogenesis","pmids":["34344693"],"is_preprint":false},{"year":2021,"finding":"CXXC5 binds to the proximal MYCL1 promoter to repress MYCL1 transcription in quiescent hepatic stellate cells (HSCs); loss of CXXC5 during HSC activation removes CpG methylation and acquires acetylated H3K9/H3K27 at the MYCL1 promoter, leading to MYCL1 trans-activation and promoting HSC activation.","method":"ChIP assay, RNA-seq, bisulfite sequencing, overexpression/knockdown experiments, promoter methylation analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct promoter binding, epigenetic mechanism characterized, single lab","pmids":["34621736"],"is_preprint":false},{"year":2022,"finding":"Mycl plays a key role in proliferation of pancreatic endocrine cells; genetic ablation reduces neonatal endocrine cell proliferation; Mycl expression in adult mice stimulates β and α cell proliferation; a subset of expanded α cells give rise to insulin-producing cells after Mycl withdrawal; transient Mycl expression normalizes hyperglycemia in diabetic mice; MYCL also stimulates division of human adult cadaveric islet cells.","method":"Genetic ablation (Mycl knockout), inducible Mycl expression in mice, β-cell mass quantification, glucose tolerance tests, human islet cell culture","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — genetic gain and loss-of-function in mice plus human islet validation, multiple functional readouts","pmids":["35145326"],"is_preprint":false}],"current_model":"MYCL (L-Myc) is a nuclear bHLH-LZ transcription factor that heterodimerizes with MAX to bind CACGTG E-box promoter elements, activates transcriptional programs including ribosomal biogenesis genes, cooperates with activated RAS to transform cells, and is phosphorylated at N-terminal serines (38/42) by GSK-3β downstream of PKC; in dendritic cells it is induced by IRF8/PU.1 and recruits the EP400 histone acetyltransferase complex (as exemplified by MCPyV ST-MYCL-EP400), while in SCLC its activation—often through RLF-MYCL gene fusion—drives tumor progression via RNA Pol I-dependent rRNA synthesis."},"narrative":{"teleology":[{"year":1985,"claim":"Identification of MYCL as a third myc-family oncogene amplified in SCLC established that the MYC family comprised at least three paralogs with distinct genomic loci and tumor-type associations.","evidence":"Southern/Northern blot hybridization and gene mapping in SCLC tumor DNA","pmids":["2997622"],"confidence":"High","gaps":["No protein product yet characterized","Functional relationship to c-Myc and N-Myc undefined"]},{"year":1988,"claim":"Demonstration that MYCL encodes phosphorylated nuclear proteins (p60/p66) from alternatively spliced mRNAs, and cooperates with activated RAS to transform cells (albeit at 1–10% of c-Myc efficiency), established it as a bona fide nuclear oncoprotein with weaker transforming potency than its paralogs.","evidence":"Cotransformation assays in rat embryo fibroblasts, subcellular fractionation, immunoprecipitation, nude mouse tumorigenicity","pmids":["2457153","3054516","2827002"],"confidence":"High","gaps":["DNA-binding specificity unknown","Basis for weaker transforming activity unresolved","Kinase responsible for phosphorylation unidentified"]},{"year":1991,"claim":"Discovery of RLF-MYCL gene fusions in SCLC cell lines revealed a specific activation mechanism—intrachromosomal rearrangement on 1p32—that deregulates L-Myc expression rather than creating a novel fusion oncoprotein.","evidence":"cDNA cloning, Southern blot, pulsed-field gel electrophoresis, and physical mapping in two independent SCLC lines","pmids":["1851085","1649386"],"confidence":"High","gaps":["In vivo oncogenic role of the fusion not yet tested in animal models","Frequency of RLF-MYCL fusion in primary SCLC tumors unknown"]},{"year":1992,"claim":"Mapping the transcriptional activation domain and identifying GSK-3β phosphorylation at serines 38/42 explained both why L-Myc has weaker transforming activity (~5% of c-Myc transactivation) and how PKC signaling modulates L-Myc post-translationally.","evidence":"GAL4-fusion transactivation assays, L-Myc/c-Myc domain-swap chimeras, in vitro kinase assay with GSK-3β, site-directed mutagenesis","pmids":["1620120","1312697"],"confidence":"High","gaps":["Functional consequence of S38/S42 phosphorylation on transcriptional activity or protein stability not resolved","Whether GSK-3β phosphorylation requires a priming kinase in vivo"]},{"year":1993,"claim":"Demonstrating that L-Myc heterodimerizes with MAX via its bHLH-LZ domain to bind CACGTG E-boxes unified L-Myc with the broader Myc-MAX network and identified its DNA-binding specificity.","evidence":"PCR-based binding site selection with purified recombinant proteins, domain mutagenesis of BR/HLH/LZ regions, cotransfection with MAX","pmids":["8455937"],"confidence":"High","gaps":["Genome-wide binding targets not mapped","Whether L-Myc competes with or complements c-Myc/N-Myc for MAX in vivo"]},{"year":1996,"claim":"The finding that Mycl-null mice are viable with no gross developmental abnormalities—despite L-Myc expression in developing kidney, lung, and brain—indicated functional redundancy with other Myc family members during embryogenesis.","evidence":"Gene targeting (knockout), RNA in situ hybridization, histology, BrdU proliferation assays","pmids":["8657155"],"confidence":"High","gaps":["Subtle phenotypes in specific cell populations not examined","Compound Myc family knockouts not tested"]},{"year":2004,"claim":"Identification of an IRES in the MYCL 5′ UTR that accounts for all translation initiation revealed a cap-independent translational control mechanism, distinguishing MYCL from c-Myc regulation.","evidence":"Bicistronic reporter assays with deletion mapping and RNA secondary structure modeling","pmids":["14730027"],"confidence":"High","gaps":["Trans-acting IRES factors not identified","Physiological conditions under which IRES-dependent translation predominates unknown"]},{"year":2014,"claim":"Discovery that Mycl is selectively induced in dendritic cells under IRF8 control—and that its loss impairs CD103+ cDC1 numbers and T-cell priming during infection—identified the first non-oncogenic physiological function of MYCL.","evidence":"Mycl(gfp) knock-in reporter mice, Mycl-deficient mice, Listeria and VSV infection models, flow cytometry","pmids":["24509714"],"confidence":"High","gaps":["Direct transcriptional targets mediating DC function not mapped","Whether MYCL is required in all DC subsets or only cDC1s"]},{"year":2016,"claim":"Showing that MYCL drives pre-rRNA synthesis and ribosomal biogenesis gene programs in SCLC—and that its conditional deletion strongly suppresses tumor formation in two Rb/p53-deleted mouse models—established a specific mechanistic link between L-Myc transcriptional activity and RNA Pol I-dependent biosynthesis in tumorigenesis.","evidence":"Conditional Mycl knockout in two SCLC GEMMs, RNA-seq, pre-rRNA synthesis assay, RNA Pol I inhibitor treatment","pmids":["27298335"],"confidence":"High","gaps":["Whether MYCL directly binds rDNA promoters or acts indirectly through Pol I cofactors","Therapeutic window of Pol I inhibition for MYCL-driven SCLC"]},{"year":2017,"claim":"The finding that MCPyV Small T antigen binds MYCL and recruits the EP400 histone acetyltransferase complex to gene promoters revealed a viral hijacking mechanism that repurposes MYCL as a chromatin-remodeling effector essential for Merkel cell carcinoma viability.","evidence":"IP-mass spectrometry, reciprocal Co-IP, ChIP-seq, RNA-seq, genome-wide CRISPR screen, transformation assay","pmids":["29028833"],"confidence":"High","gaps":["Whether endogenous MYCL-EP400 interaction operates outside the viral context","Structural basis of ST-MYCL-EP400 assembly"]},{"year":2021,"claim":"CRISPR-engineered Rlf-Mycl fusion mice demonstrated that this fusion is a bona fide oncogenic driver accelerating SCLC formation and metastasis, while parallel studies defined the IRF8/PU.1 enhancer logic controlling the c-Myc-to-L-Myc switch in DC differentiation, solidifying MYCL's dual roles in cancer and immunity.","evidence":"CRISPR/Cas9 somatic mouse model for Rlf-Mycl with tumor/metastasis quantification; IRF8 mutant and enhancer-deletion reporter mice for DC studies","pmids":["34344693","34958351"],"confidence":"High","gaps":["Therapeutic vulnerabilities specific to RLF-MYCL SCLC not identified","How IRF8/PU.1-dependent MYCL induction coordinates with cell-cycle exit in DCs"]},{"year":2022,"claim":"Demonstration that MYCL drives pancreatic endocrine cell proliferation—including human β-cells—and that transient expression normalizes hyperglycemia in diabetic mice opened a regenerative medicine dimension for MYCL beyond oncology and immunology.","evidence":"Mycl knockout and inducible expression in mice, glucose tolerance tests, human cadaveric islet cell culture","pmids":["35145326"],"confidence":"High","gaps":["Risk of oncogenic transformation from therapeutic MYCL activation in β-cells","Downstream targets mediating β-cell proliferation not defined","Long-term functional capacity of MYCL-expanded β-cells unknown"]},{"year":null,"claim":"Key unresolved questions include the genome-wide direct target repertoire of MYCL across cell types, the structural basis for its weaker transactivation compared to c-Myc, whether endogenous MYCL-EP400 interaction operates outside viral contexts, and how MYCL's biosynthetic programs can be therapeutically exploited or suppressed in cancer and regenerative settings.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal structure of MYCL-MAX-DNA complex","Comprehensive ChIP-seq atlas across normal tissues lacking","Functional consequence of S38/S42 phosphorylation in vivo not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[13,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,18,22,23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,18,22,23,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7,22,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,24,25]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[23]}],"complexes":["MYC-MAX heterodimer","ST-MYCL-EP400 complex"],"partners":["MAX","EP400","IRF8","MXD1","RLF","MCPYV ST"],"other_free_text":[]},"mechanistic_narrative":"MYCL (L-Myc) is a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor that heterodimerizes with MAX to bind CACGTG E-box elements and activate gene expression programs controlling biosynthetic processes including ribosomal biogenesis and cell proliferation [PMID:8455937, PMID:27298335]. Its N-terminal transactivation domain is weaker than that of c-Myc, yielding approximately 5% transcriptional activity and correspondingly reduced RAS-cooperative transformation efficiency, yet it retains full oncogenic potential when deregulated—most notably through RLF-MYCL gene fusions that drive small cell lung cancer (SCLC) progression and metastasis [PMID:1620120, PMID:34344693]. MYCL is phosphorylated at serines 38 and 42 by GSK-3β downstream of PKC signaling, its translation is directed by an internal ribosome entry segment in the 5′ UTR, and it is transcriptionally regulated by IRF8/PU.1 during dendritic cell specification where it controls a biosynthetic program in mature conventional DCs that is reciprocally antagonized by MXD1 [PMID:1312697, PMID:14730027, PMID:34958351, PMID:32071205]. Beyond immune and neoplastic contexts, MYCL drives proliferation of pancreatic endocrine cells and can stimulate β-cell expansion sufficient to normalize hyperglycemia in diabetic mice [PMID:35145326]."},"prefetch_data":{"uniprot":{"accession":"P12524","full_name":"Protein L-Myc","aliases":["Class E basic helix-loop-helix protein 38","bHLHe38","Protein L-Myc-1","V-myc myelocytomatosis viral oncogene homolog"],"length_aa":364,"mass_kda":40.3,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P12524/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYCL","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYCL","total_profiled":1310},"omim":[{"mim_id":"310310","title":"MYCL-RELATED PROCESSED GENE; MYCL2","url":"https://www.omim.org/entry/310310"},{"mim_id":"256700","title":"NEUROBLASTOMA, SUSCEPTIBILITY TO, 1; NBLST1","url":"https://www.omim.org/entry/256700"},{"mim_id":"164940","title":"FGR PROTOONCOGENE, SRC FAMILY TYROSINE KINASE; FGR","url":"https://www.omim.org/entry/164940"},{"mim_id":"164850","title":"MYCL PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYCL","url":"https://www.omim.org/entry/164850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":63.9},{"tissue":"skin 1","ntpm":37.4}],"url":"https://www.proteinatlas.org/search/MYCL"},"hgnc":{"alias_symbol":["LMYC","bHLHe38"],"prev_symbol":["MYCL1"]},"alphafold":{"accession":"P12524","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12524","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12524-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12524-F1-predicted_aligned_error_v6.png","plddt_mean":63.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYCL","jax_strain_url":"https://www.jax.org/strain/search?query=MYCL"},"sequence":{"accession":"P12524","fasta_url":"https://rest.uniprot.org/uniprotkb/P12524.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12524/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12524"}},"corpus_meta":[{"pmid":"2997622","id":"PMC_2997622","title":"L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer.","date":"1985","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2997622","citation_count":663,"is_preprint":false},{"pmid":"3322939","id":"PMC_3322939","title":"The human myc gene family: structure and activity of L-myc and an L-myc pseudogene.","date":"1987","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/3322939","citation_count":126,"is_preprint":false},{"pmid":"2827002","id":"PMC_2827002","title":"Structure and expression of the human L-myc gene reveal a complex pattern of alternative mRNA processing.","date":"1988","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2827002","citation_count":115,"is_preprint":false},{"pmid":"29028833","id":"PMC_29028833","title":"Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis.","date":"2017","source":"PLoS 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journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11494234","citation_count":7,"is_preprint":false},{"pmid":"8630982","id":"PMC_8630982","title":"L-MYC allelotype in renal cell carcinoma.","date":"1996","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/8630982","citation_count":7,"is_preprint":false},{"pmid":"1683040","id":"PMC_1683040","title":"Restriction fragment length polymorphism of the L-myc gene and susceptibility to metastasis in genitourinary cancers.","date":"1991","source":"Urologia internationalis","url":"https://pubmed.ncbi.nlm.nih.gov/1683040","citation_count":7,"is_preprint":false},{"pmid":"34257619","id":"PMC_34257619","title":"MYCL1 Amplification and Expression of L-Myc and c-Myc in Surgically Resected Small-Cell Lung Carcinoma.","date":"2021","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/34257619","citation_count":6,"is_preprint":false},{"pmid":"18566574","id":"PMC_18566574","title":"L-myc gene polymorphism and risk of thyroid cancer.","date":"2008","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18566574","citation_count":6,"is_preprint":false},{"pmid":"37857701","id":"PMC_37857701","title":"Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37857701","citation_count":6,"is_preprint":false},{"pmid":"27930960","id":"PMC_27930960","title":"Loss of Rearranged L-Myc Fusion (RLF) results in defects in heart development in the mouse.","date":"2016","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/27930960","citation_count":6,"is_preprint":false},{"pmid":"37105559","id":"PMC_37105559","title":"Alterations and Co-Occurrence of C-MYC, N-MYC, and L-MYC Expression are Related to Clinical Outcomes in Various Cancers.","date":"2023","source":"International journal of stem cells","url":"https://pubmed.ncbi.nlm.nih.gov/37105559","citation_count":5,"is_preprint":false},{"pmid":"19596922","id":"PMC_19596922","title":"Role of L-MYC polymorphism in oral squamous cell carcinoma in Turkey.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19596922","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43217,"output_tokens":6167,"usd":0.111078},"stage2":{"model":"claude-opus-4-6","input_tokens":9866,"output_tokens":3211,"usd":0.194408},"total_usd":0.305486,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1985,\n      \"finding\": \"L-myc (MYCL) was identified as a third myc-related gene, amplified and expressed in human small cell lung cancer (SCLC), mapping to human chromosome 1p32, distinct from c-myc and N-myc loci.\",\n      \"method\": \"Southern blot hybridization, gene mapping, Northern blot\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational discovery with multiple orthogonal methods, >663 citations, widely replicated\",\n      \"pmids\": [\"2997622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Human L-myc gene has a three-exon organization similar to c-myc and N-myc, encodes a 364 amino acid protein retaining five of seven conserved Myc homology regions, and can cooperate with mutant Ha-ras to transform rat embryo fibroblasts (cotransformation assay).\",\n      \"method\": \"Nucleotide sequencing, cotransformation assay in rat embryo fibroblasts\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct transformation assay with structural characterization, >126 citations\",\n      \"pmids\": [\"3322939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"L-myc gene generates multiple mRNA species from a single gene by alternative splicing of introns 1 and 2 and use of alternative polyadenylation signals; some transcripts encode a truncated protein with a novel carboxy-terminal end.\",\n      \"method\": \"Northern blot, cDNA sequencing, mRNA structure analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — detailed molecular characterization, >115 citations\",\n      \"pmids\": [\"2827002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"L-myc cooperates with activated ras to transform primary rat embryo fibroblasts, but with only 1–10% of the efficiency of c-myc; L-myc/ras transformants are tumorigenic in nude mice.\",\n      \"method\": \"Cotransformation assay with activated ras in rat embryo fibroblasts, nude mouse tumorigenicity assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct functional assay replicated across labs\",\n      \"pmids\": [\"2457153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"L-myc proteins p60 and p66 (molecular masses 60 and 66 kDa) are phosphorylated nuclear proteins localized to the nuclear matrix fraction; both arise from the 3.9 kb mRNA; the short-lived proteins have differential stability based on the mRNA isoform.\",\n      \"method\": \"Immunoprecipitation, subcellular fractionation, in vitro translation, Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — nuclear localization by fractionation with protein characterization, >45 citations\",\n      \"pmids\": [\"3054516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"L-myc protein phosphorylation is rapidly increased by phorbol ester (TPA) treatment or serum, correlating with protein kinase C activation; three polypeptides of 60–66 kDa are differentially phosphorylated forms of a common precursor (alkaline phosphatase converts them to a single ~59 kDa band).\",\n      \"method\": \"Immunoprecipitation with [35S]methionine and [32P]orthophosphate labeling, alkaline phosphatase treatment, phorbol ester stimulation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assay with multiple orthogonal methods demonstrating PTM\",\n      \"pmids\": [\"2540955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Eµ-L-myc transgenic mice show preferential L-myc expression in T cells, thymic hyperplasia, and predisposition to T-cell lymphomas; the L-myc transgene can substitute for c- or N-myc in generating lymphoid neoplasms without detectable endogenous myc expression.\",\n      \"method\": \"Transgenic mouse model, FACS, histopathology, Northern blot\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with direct phenotypic readout\",\n      \"pmids\": [\"2120050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Two SCLC cell lines express chimeric RLF-L-myc fusion proteins arising from intrachromosomal rearrangements that place the regulatory region and first exon of the novel gene RLF upstream of L-myc, representing an activation mechanism for the L-myc proto-oncogene.\",\n      \"method\": \"cDNA cloning, Northern blot, Southern blot, immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — molecular characterization of fusion protein across two independent cell lines\",\n      \"pmids\": [\"1851085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"RLF and L-myc genes are physically linked on chromosome 1p32 within <800 kb; their fusion results from intrachromosomal rearrangements producing identical chimeric proteins in independent SCLC cell lines.\",\n      \"method\": \"Somatic cell hybrid mapping, pulsed-field gel electrophoresis, Southern blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical mapping with functional context, >29 citations\",\n      \"pmids\": [\"1649386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"L-myc translation initiates from both an AUG codon in exon 2 and an unusual non-AUG (CUG) site in intron 1; the CUG-initiated protein (p65) also possesses transforming activity in rat embryo cells.\",\n      \"method\": \"In vitro translation, transfection/transformation assay in rat embryo cells, immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical + functional transformation assay\",\n      \"pmids\": [\"1849244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The N-terminal transcriptional activation domain of L-Myc activates transcription when fused to the GAL4 DNA-binding domain, but at only ~5% of c-Myc activity; chimera experiments show the activation domain potency determines cotransforming efficiency of L-Myc vs c-Myc.\",\n      \"method\": \"GAL4 fusion transcription activation assays, cotransformation assay in rat embryo fibroblasts, L-Myc/c-Myc chimeras\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted transcription assay with domain-swap mutagenesis\",\n      \"pmids\": [\"1620120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"PKC activation by TPA induces phosphorylation of L-myc at N-terminal serine residues 38 and 42; these serines can be phosphorylated in vitro by GSK-3β; mutating them to alanine abolishes heterogeneous electrophoretic migration and TPA-induced hyperphosphorylation.\",\n      \"method\": \"In vitro mutagenesis, in vitro kinase assay with GSK-3β, phorbol ester stimulation, phosphoamino acid analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus site-directed mutagenesis, identifies specific PTM sites and writer\",\n      \"pmids\": [\"1312697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Forced L-myc expression in lens fiber cells causes severely disorganized fiber cell compartment and decreased late-stage differentiation marker (MIP26), demonstrating L-myc affects differentiation processes directly rather than through deregulated growth control; in contrast, c-myc inhibits cell cycle exit but not differentiation.\",\n      \"method\": \"αA-crystallin promoter transgenic mice, histology, molecular differentiation markers, BrdU proliferation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic approach with specific molecular readouts, contrasts L-myc vs c-myc\",\n      \"pmids\": [\"7882978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"L-Myc, like c-Myc, heterodimerizes with purified Max protein to bind the core DNA sequence CACGTG; Max expression augments L-Myc cotransforming activity; the bHLH-Zip domain of L-Myc interacts equivalently to c-Myc with Max.\",\n      \"method\": \"PCR-based binding site selection, pulldown/heterodimerization assay with bacterially synthesized proteins, cotransfection with Max expression vector\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with purified proteins plus functional transformation data\",\n      \"pmids\": [\"1620120\", \"8455937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"N- and L-Myc bind preferentially to CACGTG motifs and form heterodimeric DNA-binding complexes with Max; all three domains (BR, HLH, LZ) are required for DNA binding, while dimerization requires HLH and LZ.\",\n      \"method\": \"PCR-based binding site selection, mutational analysis of BR/HLH/LZ domains\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with mutagenesis\",\n      \"pmids\": [\"8455937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The RLF gene encodes a 1914 amino acid zinc finger protein with 16 zinc finger motifs related to the Zn-15 transcription factor; the RLF-L-myc fusions do not include zinc fingers, and transforming ability of RLF-L-myc is indistinguishable from normal L-myc, indicating rearrangement deregulates L-myc expression rather than creating a new oncogene.\",\n      \"method\": \"cDNA sequencing, transformation assay comparison\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular characterization with functional comparison\",\n      \"pmids\": [\"8545128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"L-Myc is expressed in developing kidney, lung, and brain (proliferative and differentiative zones) in mouse; homozygous L-myc null mice are viable and reproductively competent with no detectable morphological abnormalities or compensatory changes in c- or N-myc, demonstrating L-Myc is dispensable for gross embryonic development.\",\n      \"method\": \"RNA in situ hybridization, gene targeting (knockout), histological analysis, BrdU proliferation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout with comprehensive phenotypic analysis, >94 citations\",\n      \"pmids\": [\"8657155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"c-, N-, and L-myc oncoproteins all accelerate apoptosis in IL-3-dependent 32D cells after IL-3 withdrawal; however, unlike c-myc which sensitizes cells to cytotoxic drugs, N-myc and L-myc overexpression produce resistance to cytotoxic agents, identifying distinct apoptotic pathways regulated by each family member.\",\n      \"method\": \"Stable transfection in 32D hematopoietic cells, IL-3 withdrawal assay, cytotoxic drug treatment, apoptosis quantification\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/OE with defined cellular phenotype comparing family members\",\n      \"pmids\": [\"9751117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCL6 chemokine is a direct positive transcriptional target of L-Myc in 32D myeloid cells; L-Myc binds the CCL6 promoter as shown by chromatin immunoprecipitation; CCL6 coexpression with c-Myc abrogates IL-3 dependence and produces a leukemogenic phenotype.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter assays, stable transfection, tumorigenicity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct promoter binding with functional consequence\",\n      \"pmids\": [\"12782599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The 5' UTR of L-myc contains an IRES (internal ribosome entry segment) that accounts for all translation initiation from the L-myc mRNA; the ribosome entry window is upstream of the start codon, utilizing a 'land and scan' mechanism; a secondary structure model including a pseudoknot near the 5' end was derived.\",\n      \"method\": \"Bicistronic reporter assays, deletion mapping, RNA secondary structure modeling\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct functional assay with mutational mapping of IRES element\",\n      \"pmids\": [\"14730027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A SNP (rs3134615) in the 3'-UTR of MYCL1 alters the binding site for hsa-miR-1827; the rs3134615 G>T change results in altered regulation of MYCL1 expression as shown by reporter gene assays.\",\n      \"method\": \"Reporter gene assay (3'-UTR luciferase), case-control analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay demonstrates functional miRNA-binding site, single lab\",\n      \"pmids\": [\"21676885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mycl1 is selectively expressed in dendritic cells (DCs) under IRF8 transcriptional control; expression transitions from c-Myc in progenitors to L-Myc in mature DCs; Mycl1-deficient mice have reduced migratory CD103+ conventional DCs and impaired in vivo T-cell priming during Listeria and VSV infection.\",\n      \"method\": \"Mycl1(gfp) reporter knock-in mice, flow cytometry, infection models (Listeria monocytogenes, VSV), immunofluorescence\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific functional phenotype (T-cell priming) in vivo, multiple infections, >64 citations\",\n      \"pmids\": [\"24509714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"L-Myc promotes pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis in neuroendocrine preneoplastic cells; deletion of Mycl in two genetically engineered SCLC mouse models (Rb/p53-deleted) strongly suppresses tumor formation; RNA polymerase I inhibition mimics this effect.\",\n      \"method\": \"Conditional Mycl knockout in SCLC mouse models, RNA-seq, pre-rRNA synthesis assay, RNA Pol I inhibitor treatment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent genetic mouse models, multiple functional readouts, mechanistic link to rRNA synthesis\",\n      \"pmids\": [\"27298335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Merkel cell polyomavirus Small T antigen (ST) binds specifically to MYCL and recruits it to the 15-component EP400 histone acetyltransferase/chromatin remodeling complex; the ST-MYCL-EP400 complex binds gene promoters and activates their expression; MYCL and EP400 are required for MCC cell viability and cooperate with ST in cellular transformation and iPSC generation.\",\n      \"method\": \"Large-scale immunoprecipitation with mass spectrometry, reciprocal Co-IP for MAX and EP400, ChIP-seq, RNA-seq, genome-wide CRISPR-Cas9 screen, transformation assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP confirmed by MS, ChIP-seq, RNA-seq, and CRISPR screen, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29028833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYCL and MXD1 regulate a reciprocal transcriptional program during cDC1 maturation; Mycl-deficient immature cDC1s show reduced expression of genes regulating core biosynthetic processes; Mxd1-deficient mature cDC1s fail to suppress the MYCL-dependent transcriptional signature.\",\n      \"method\": \"Mycl-deficient and Mxd1-/- mice, RNA-seq, flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO of both reciprocal factors with transcriptomic readout, single lab\",\n      \"pmids\": [\"32071205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRF8 (in cooperation with PU.1 at EICEs within Mycl enhancers) drives the transition from c-Myc to L-Myc during DC specification; high IRF8 levels are required for this transition in cDC1s and pDCs; IRF8 also contributes to MYC repression; MYCL is most highly expressed in DCs that have exited the cell cycle.\",\n      \"method\": \"Reporter mice for MYC, MYCL, Geminin, CDT1; IRF8 mutant mice; Irf8 enhancer deletion (+41kb); flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic mouse models with reporters, identifies specific transcription factor and enhancer element\",\n      \"pmids\": [\"34958351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RLF-MYCL fusion accelerates SCLC tumor formation, proliferation, and metastatic dissemination in a CRISPR/Cas9-engineered mouse model; gene expression similarities confirmed between mouse and human RLF-MYCL SCLC, establishing RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC.\",\n      \"method\": \"CRISPR/Cas9 somatic genome editing to generate Rlf-Mycl mouse model, RNA-seq, tumor growth and metastasis quantification\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetically engineered mouse model with direct causal evidence of fusion in oncogenesis\",\n      \"pmids\": [\"34344693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CXXC5 binds to the proximal MYCL1 promoter to repress MYCL1 transcription in quiescent hepatic stellate cells (HSCs); loss of CXXC5 during HSC activation removes CpG methylation and acquires acetylated H3K9/H3K27 at the MYCL1 promoter, leading to MYCL1 trans-activation and promoting HSC activation.\",\n      \"method\": \"ChIP assay, RNA-seq, bisulfite sequencing, overexpression/knockdown experiments, promoter methylation analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct promoter binding, epigenetic mechanism characterized, single lab\",\n      \"pmids\": [\"34621736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mycl plays a key role in proliferation of pancreatic endocrine cells; genetic ablation reduces neonatal endocrine cell proliferation; Mycl expression in adult mice stimulates β and α cell proliferation; a subset of expanded α cells give rise to insulin-producing cells after Mycl withdrawal; transient Mycl expression normalizes hyperglycemia in diabetic mice; MYCL also stimulates division of human adult cadaveric islet cells.\",\n      \"method\": \"Genetic ablation (Mycl knockout), inducible Mycl expression in mice, β-cell mass quantification, glucose tolerance tests, human islet cell culture\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain and loss-of-function in mice plus human islet validation, multiple functional readouts\",\n      \"pmids\": [\"35145326\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYCL (L-Myc) is a nuclear bHLH-LZ transcription factor that heterodimerizes with MAX to bind CACGTG E-box promoter elements, activates transcriptional programs including ribosomal biogenesis genes, cooperates with activated RAS to transform cells, and is phosphorylated at N-terminal serines (38/42) by GSK-3β downstream of PKC; in dendritic cells it is induced by IRF8/PU.1 and recruits the EP400 histone acetyltransferase complex (as exemplified by MCPyV ST-MYCL-EP400), while in SCLC its activation—often through RLF-MYCL gene fusion—drives tumor progression via RNA Pol I-dependent rRNA synthesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MYCL (L-Myc) is a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor that heterodimerizes with MAX to bind CACGTG E-box elements and activate gene expression programs controlling biosynthetic processes including ribosomal biogenesis and cell proliferation [PMID:8455937, PMID:27298335]. Its N-terminal transactivation domain is weaker than that of c-Myc, yielding approximately 5% transcriptional activity and correspondingly reduced RAS-cooperative transformation efficiency, yet it retains full oncogenic potential when deregulated—most notably through RLF-MYCL gene fusions that drive small cell lung cancer (SCLC) progression and metastasis [PMID:1620120, PMID:34344693]. MYCL is phosphorylated at serines 38 and 42 by GSK-3β downstream of PKC signaling, its translation is directed by an internal ribosome entry segment in the 5′ UTR, and it is transcriptionally regulated by IRF8/PU.1 during dendritic cell specification where it controls a biosynthetic program in mature conventional DCs that is reciprocally antagonized by MXD1 [PMID:1312697, PMID:14730027, PMID:34958351, PMID:32071205]. Beyond immune and neoplastic contexts, MYCL drives proliferation of pancreatic endocrine cells and can stimulate β-cell expansion sufficient to normalize hyperglycemia in diabetic mice [PMID:35145326].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Identification of MYCL as a third myc-family oncogene amplified in SCLC established that the MYC family comprised at least three paralogs with distinct genomic loci and tumor-type associations.\",\n      \"evidence\": \"Southern/Northern blot hybridization and gene mapping in SCLC tumor DNA\",\n      \"pmids\": [\"2997622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No protein product yet characterized\", \"Functional relationship to c-Myc and N-Myc undefined\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstration that MYCL encodes phosphorylated nuclear proteins (p60/p66) from alternatively spliced mRNAs, and cooperates with activated RAS to transform cells (albeit at 1–10% of c-Myc efficiency), established it as a bona fide nuclear oncoprotein with weaker transforming potency than its paralogs.\",\n      \"evidence\": \"Cotransformation assays in rat embryo fibroblasts, subcellular fractionation, immunoprecipitation, nude mouse tumorigenicity\",\n      \"pmids\": [\"2457153\", \"3054516\", \"2827002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding specificity unknown\", \"Basis for weaker transforming activity unresolved\", \"Kinase responsible for phosphorylation unidentified\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Discovery of RLF-MYCL gene fusions in SCLC cell lines revealed a specific activation mechanism—intrachromosomal rearrangement on 1p32—that deregulates L-Myc expression rather than creating a novel fusion oncoprotein.\",\n      \"evidence\": \"cDNA cloning, Southern blot, pulsed-field gel electrophoresis, and physical mapping in two independent SCLC lines\",\n      \"pmids\": [\"1851085\", \"1649386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo oncogenic role of the fusion not yet tested in animal models\", \"Frequency of RLF-MYCL fusion in primary SCLC tumors unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Mapping the transcriptional activation domain and identifying GSK-3β phosphorylation at serines 38/42 explained both why L-Myc has weaker transforming activity (~5% of c-Myc transactivation) and how PKC signaling modulates L-Myc post-translationally.\",\n      \"evidence\": \"GAL4-fusion transactivation assays, L-Myc/c-Myc domain-swap chimeras, in vitro kinase assay with GSK-3β, site-directed mutagenesis\",\n      \"pmids\": [\"1620120\", \"1312697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of S38/S42 phosphorylation on transcriptional activity or protein stability not resolved\", \"Whether GSK-3β phosphorylation requires a priming kinase in vivo\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrating that L-Myc heterodimerizes with MAX via its bHLH-LZ domain to bind CACGTG E-boxes unified L-Myc with the broader Myc-MAX network and identified its DNA-binding specificity.\",\n      \"evidence\": \"PCR-based binding site selection with purified recombinant proteins, domain mutagenesis of BR/HLH/LZ regions, cotransfection with MAX\",\n      \"pmids\": [\"8455937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide binding targets not mapped\", \"Whether L-Myc competes with or complements c-Myc/N-Myc for MAX in vivo\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The finding that Mycl-null mice are viable with no gross developmental abnormalities—despite L-Myc expression in developing kidney, lung, and brain—indicated functional redundancy with other Myc family members during embryogenesis.\",\n      \"evidence\": \"Gene targeting (knockout), RNA in situ hybridization, histology, BrdU proliferation assays\",\n      \"pmids\": [\"8657155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subtle phenotypes in specific cell populations not examined\", \"Compound Myc family knockouts not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of an IRES in the MYCL 5′ UTR that accounts for all translation initiation revealed a cap-independent translational control mechanism, distinguishing MYCL from c-Myc regulation.\",\n      \"evidence\": \"Bicistronic reporter assays with deletion mapping and RNA secondary structure modeling\",\n      \"pmids\": [\"14730027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting IRES factors not identified\", \"Physiological conditions under which IRES-dependent translation predominates unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that Mycl is selectively induced in dendritic cells under IRF8 control—and that its loss impairs CD103+ cDC1 numbers and T-cell priming during infection—identified the first non-oncogenic physiological function of MYCL.\",\n      \"evidence\": \"Mycl(gfp) knock-in reporter mice, Mycl-deficient mice, Listeria and VSV infection models, flow cytometry\",\n      \"pmids\": [\"24509714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating DC function not mapped\", \"Whether MYCL is required in all DC subsets or only cDC1s\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that MYCL drives pre-rRNA synthesis and ribosomal biogenesis gene programs in SCLC—and that its conditional deletion strongly suppresses tumor formation in two Rb/p53-deleted mouse models—established a specific mechanistic link between L-Myc transcriptional activity and RNA Pol I-dependent biosynthesis in tumorigenesis.\",\n      \"evidence\": \"Conditional Mycl knockout in two SCLC GEMMs, RNA-seq, pre-rRNA synthesis assay, RNA Pol I inhibitor treatment\",\n      \"pmids\": [\"27298335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYCL directly binds rDNA promoters or acts indirectly through Pol I cofactors\", \"Therapeutic window of Pol I inhibition for MYCL-driven SCLC\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The finding that MCPyV Small T antigen binds MYCL and recruits the EP400 histone acetyltransferase complex to gene promoters revealed a viral hijacking mechanism that repurposes MYCL as a chromatin-remodeling effector essential for Merkel cell carcinoma viability.\",\n      \"evidence\": \"IP-mass spectrometry, reciprocal Co-IP, ChIP-seq, RNA-seq, genome-wide CRISPR screen, transformation assay\",\n      \"pmids\": [\"29028833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous MYCL-EP400 interaction operates outside the viral context\", \"Structural basis of ST-MYCL-EP400 assembly\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CRISPR-engineered Rlf-Mycl fusion mice demonstrated that this fusion is a bona fide oncogenic driver accelerating SCLC formation and metastasis, while parallel studies defined the IRF8/PU.1 enhancer logic controlling the c-Myc-to-L-Myc switch in DC differentiation, solidifying MYCL's dual roles in cancer and immunity.\",\n      \"evidence\": \"CRISPR/Cas9 somatic mouse model for Rlf-Mycl with tumor/metastasis quantification; IRF8 mutant and enhancer-deletion reporter mice for DC studies\",\n      \"pmids\": [\"34344693\", \"34958351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic vulnerabilities specific to RLF-MYCL SCLC not identified\", \"How IRF8/PU.1-dependent MYCL induction coordinates with cell-cycle exit in DCs\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that MYCL drives pancreatic endocrine cell proliferation—including human β-cells—and that transient expression normalizes hyperglycemia in diabetic mice opened a regenerative medicine dimension for MYCL beyond oncology and immunology.\",\n      \"evidence\": \"Mycl knockout and inducible expression in mice, glucose tolerance tests, human cadaveric islet cell culture\",\n      \"pmids\": [\"35145326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Risk of oncogenic transformation from therapeutic MYCL activation in β-cells\", \"Downstream targets mediating β-cell proliferation not defined\", \"Long-term functional capacity of MYCL-expanded β-cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the genome-wide direct target repertoire of MYCL across cell types, the structural basis for its weaker transactivation compared to c-Myc, whether endogenous MYCL-EP400 interaction operates outside viral contexts, and how MYCL's biosynthetic programs can be therapeutically exploited or suppressed in cancer and regenerative settings.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of MYCL-MAX-DNA complex\", \"Comprehensive ChIP-seq atlas across normal tissues lacking\", \"Functional consequence of S38/S42 phosphorylation in vivo not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 18, 22, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 18, 22, 23, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 22, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 24, 25]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\n      \"MYC-MAX heterodimer\",\n      \"ST-MYCL-EP400 complex\"\n    ],\n    \"partners\": [\n      \"MAX\",\n      \"EP400\",\n      \"IRF8\",\n      \"MXD1\",\n      \"RLF\",\n      \"MCPyV ST\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}