{"gene":"MAML2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2004,"finding":"The t(11;19) translocation creates a WAMTP1-MAML2 (later called CRTC1-MAML2) fusion protein in which the N-terminal basic domain of MAML2 required for binding to intracellular Notch (Notch ICD) is replaced by an unrelated N-terminal sequence from WAMTP1. Mutation analysis identified two regions important for nuclear localization (amino acids 11-20) and colocalization with MAML2 and Notch1 ICD in nuclear granules (amino acids 21-42). The fusion results in upregulation of HES5 and downregulation of MASH1 in fusion-positive MECs, indicating altered Notch signaling.","method":"Cloning, mutation analysis of N-terminus, nuclear localization studies, Notch target gene expression analysis in MEC tumors","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mutagenesis, localization, target gene expression) in a single study","pmids":["14720503"],"is_preprint":false},{"year":2005,"finding":"The MECT1-MAML2 fusion protein binds to CREB, recruits p300/CBP into the CREB complex through a binding domain on MAML2, and constitutively activates CREB-dependent transcription. Blocking CREB DNA binding markedly reduced the transforming activity of MECT1-MAML2, demonstrating that constitutive CREB activation is the primary mechanism of transformation.","method":"Co-immunoprecipitation, luciferase reporter assays, dominant-negative CREB blocking, gene expression analysis, transformation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including binding assays, mutagenesis of CREB-binding activity, and functional transformation readout","pmids":["15961999"],"is_preprint":false},{"year":2005,"finding":"Small in-frame deletions within the CREB-binding domain of Mect1/Torc1 portion of the Mect1-Maml2 fusion completely abolished transforming activity in RK3E epithelial cells. Ectopic induction of Mect1-Maml2 strongly activated known cAMP/CREB-regulated genes but did not alter known Notch-regulated target genes, establishing that cAMP/CREB pathway activation (not Notch signaling) is the primary oncogenic mechanism.","method":"In-frame deletion mutagenesis, doxycycline-regulated expression, global gene expression profiling, RT-PCR validation in multiple cell lines","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis plus gene expression profiling with validation across multiple cell lines, replicated key finding from Wu et al. 2005","pmids":["16103063"],"is_preprint":false},{"year":2006,"finding":"Sustained expression of Mect1-Maml2 is required for tumor cell growth in MEC cancer cells carrying the t(11;19) translocation. RNAi-mediated knockdown of the fusion peptide caused at least 90% colony growth inhibition in MEC cell lines, while having no effect on non-MEC tumors. A rescue experiment using a mutant Mect1-Maml2 with silent changes in the RNAi target sequence partially restored growth, confirming on-target specificity.","method":"RNAi knockdown, colony formation assay, in vivo xenograft, rescue experiment with RNAi-resistant mutant","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — RNAi plus rescue experiment with multiple cell lines and in vivo validation","pmids":["16652146"],"is_preprint":false},{"year":2007,"finding":"The CRTC1-MAML2 gene fusion is present in 50% of clear cell hidradenomas (benign skin tumors), demonstrating that the fusion's oncogenic activity extends beyond salivary and bronchial gland tumors. All fusion-positive hidradenomas had clear cell morphology, while all fusion-negative tumors lacked clear cells, establishing a genotype-phenotype correlation.","method":"FISH, RT-PCR, immunohistochemistry","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 — detection methods without direct mechanistic functional assays, but clear genotype-phenotype correlation","pmids":["17334997"],"is_preprint":false},{"year":2007,"finding":"A novel MLL-MAML2 fusion gene is created by inv(11)(q21q23) in secondary AML/MDS. In the fusion, the N-terminal basic domain of MAML2 (including the Notch ICD binding site) is deleted. Luciferase assay demonstrated that MLL-MAML2 suppresses HES1 promoter activation by NOTCH1 intracellular domain, indicating dominant-negative disruption of Notch signaling.","method":"RT-PCR, sequencing, luciferase reporter assay for HES1 promoter","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 — functional luciferase assay demonstrating mechanistic effect on Notch target, single lab","pmids":["17551948"],"is_preprint":false},{"year":2013,"finding":"CRTC1-MAML2 fusion oncogene is required for growth and survival of fusion-positive MEC cells in vitro and in vivo. The oncoprotein induces upregulation of the EGFR ligand Amphiregulin (AREG) by co-activating transcription factor CREB, and AREG subsequently activates EGFR signaling in an autocrine manner. CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition.","method":"RNA interference, gene expression analysis, pharmacological EGFR inhibition, in vitro growth assays, in vivo xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNAi, pharmacological inhibition, in vitro and in vivo) establishing the CRTC1-MAML2→CREB→AREG→EGFR axis","pmids":["23975434"],"is_preprint":false},{"year":2014,"finding":"The CRTC1/MAML2 (C1/M2) oncoprotein interacts with MYC proteins and activates MYC transcription targets including genes involved in cell growth, metabolism, survival, and tumorigenesis. The C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation, representing a gain-of-function activity beyond CREB and NOTCH pathway dysregulation.","method":"Co-immunoprecipitation, gene expression profiling, transformation assays in human MEC tumor cells with t(11;19)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional transformation assay with loss-of-interaction validation","pmids":["25071166"],"is_preprint":false},{"year":2015,"finding":"A peptide derived from transactivation domain 1 (TAD1) of MAML2 binds directly to the CBP KIX domain with micromolar affinity. An ~20-residue segment within this peptide, conserved in MAML2 orthologs and paralogs, binds a KIX surface previously shown to bind MLL1, forming an alpha-helix similar to the MLL1-KIX interaction. Because CRTC1/3-MAML2 fusion proteins are constitutively nuclear, this provides the mechanism for constitutive CBP/p300 recruitment to CREB targets.","method":"In vitro binding assay (peptide-KIX domain), NMR structural analysis, sequence conservation analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted binding with structural characterization of the MAML2 TAD1-KIX interface","pmids":["26274502"],"is_preprint":false},{"year":2016,"finding":"Stilbenoids (resveratrol and pterostilbene) induce de novo methylation at the MAML2 enhancer, recruiting DNMT3B and reducing OCT1 transcription factor occupancy, leading to transcriptional silencing of MAML2 and downregulation of NOTCH target genes in breast cancer cells. Increased repressive histone marks and decreased activating marks accompany the enhanced DNA methylation.","method":"Genome-wide DNA methylation analysis (Illumina 450K), ChIP assay, immunohistochemistry, transcriptomics","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and methylation analysis with functional gene expression consequence, single lab","pmids":["27207652"],"is_preprint":false},{"year":2018,"finding":"CRTC1-MAML2 fusion induces transcription of the lncRNA LINC00473, which was the top downregulated target upon CRTC1-MAML2 depletion. LINC00473 induction requires CRTC1-MAML2's ability to activate CREB-mediated transcription. LINC00473 localizes predominantly to the nucleus and binds the cAMP signaling component NONO, enhancing CRTC1-MAML2-mediated CREB transcription in a positive feedback loop. LINC00473 depletion reduced MEC cell proliferation and blocked in vivo tumor growth.","method":"Gene expression profiling, RNA interference, RIP assay, RNA in situ hybridization, in vivo xenograft, loss-of-function studies","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RIP, RNAi, in vitro and in vivo) establishing LINC00473 as a CRTC1-MAML2 downstream mediator","pmids":["29353885"],"is_preprint":false},{"year":2019,"finding":"YAP1-MAML2 fusions are highly recurrent in poromas (88.5%) and porocarcinomas (63.6%). The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic role through YAP/TEAD-dependent transcription.","method":"RNA sequencing, RT-PCR, FISH, TEAD reporter luciferase assay, anchorage-independent growth assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — functional TEAD reporter assay plus transformation assay, multiple orthogonal detection methods","pmids":["31145701"],"is_preprint":false},{"year":2021,"finding":"CRTC1-MAML2 is the major oncogenic driver of MEC in vivo: doxycycline-induced CRTC1-MAML2 knockdown blocked established MEC xenograft growth, and Cre-induced CRTC1-MAML2 expression in a conditional transgenic mouse model caused 100% penetrant salivary gland tumor formation resembling human MEC. Altered p16-CDK4/6-RB pathway activity was identified as a cooperating event, and cotargeting AREG/EGFR (erlotinib) and CDK4/6 (palbociclib) produced enhanced antitumor responses.","method":"Inducible RNAi knockdown in xenografts, conditional transgenic mouse model, molecular pathway analysis, combination drug treatment in vitro and in vivo","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 — conditional transgenic model with 100% penetrance plus xenograft rescue, multiple orthogonal methods establishing CRTC1-MAML2 as causal driver","pmids":["33830080"],"is_preprint":false},{"year":2021,"finding":"CRTC1/MAML2 (C1/M2) induces transcriptional activation of the non-canonical PGC-1α splice variant PGC-1α4, which drives PPARγ-mediated IGF-1 expression in an autocrine circuit. C1/M2-positive MEC cells are selectively sensitive to IGF-1R inhibition and PPARγ inverse agonists, revealing a PGC-1α-IGF-1 signaling axis as a vulnerability in fusion-positive tumors.","method":"Gene expression profiling, small-molecule drug screens, knockdown studies, IGF-1R inhibitor treatment in cell lines and primary tumors","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (transcriptomics, pharmacological, genetic) across cell lines and primary tumors","pmids":["33626346"],"is_preprint":false},{"year":2021,"finding":"LINC01152 positively regulates MAML2 in GBM cells by sponging miR-466 and by recruiting SRSF1. In turn, the RBPJ/MAML2 transcription complex activates transcription of LINC01152, forming a positive feedback loop that promotes GBM tumorigenesis via the Notch signaling pathway.","method":"RNA pulldown assay, luciferase reporter assay, RIP assay, ChIP assay, functional proliferation/apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding assays (pulldown, RIP, ChIP) plus functional readouts, single lab","pmids":["33483471"],"is_preprint":false},{"year":2022,"finding":"YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Expression of YAP1-MAML2 in mice induces meningioma-like tumors resembling NF2 mutant meningiomas by gene expression. Treatment with YAP-TEAD inhibitors is sufficient to inhibit viability of YAP1-MAML2-driven mouse tumors ex vivo. Constitutively active YAP1 (S127/397A-YAP1) alone is sufficient to induce similar tumors, establishing that the YAP component drives oncogenesis.","method":"Mouse in vivo tumor induction, gene expression profiling, YAP-TEAD inhibitor treatment ex vivo, constitutively active YAP1 mutant expression","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo mouse model plus pharmacological TEAD inhibition and active-site mutant validation, multiple orthogonal approaches","pmids":["36008139"],"is_preprint":false},{"year":2023,"finding":"A pathogenic MAML2 variant was identified in a patient with congenital hypothyroidism due to dyshormonogenesis. The MAML2 variant exerted a dominant-negative effect on canonical Notch signaling and on thyroid hormone biosynthesis. In zebrafish and mouse models, Notch pathway inhibition (γ-secretase inhibitor) recapitulated hypothyroidism and dyshormonogenesis. HES1, a Notch target transactivated by MAML2, directly regulates thyroid hormone biosynthesis gene expression.","method":"Next-generation sequencing, in vitro functional assays in HEK293T and Nthy-ori 3.1 cells, zebrafish and mouse models, organoid culture, transcriptome sequencing","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems and functional assays, single lab, dominant-negative mechanism validated in vitro and in vivo","pmids":["36898841"],"is_preprint":false},{"year":2024,"finding":"YAP1-MAML2 undergoes phase separation and forms liquid-like condensates bearing hallmarks of transcriptional activity. Using a chemogenetic tool to dissolve TF condensates, phase separation was found to further upregulate a small fraction of YAP1-MAML2-regulated genes (including canonical YAP targets CTGF and CYR61) while the majority of YAP1-MAML2-regulated genes are not affected by phase separation, indicating that diffuse TF complexes can activate transcription without phase separation.","method":"Phase separation assays (live imaging, FRAP), chemogenetic dissolution of condensates, RNA-seq comparison of phase-separated vs. non-phase-separated conditions at identical protein levels","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct live imaging, FRAP, and chemogenetic tool with transcriptome-wide readout, multiple orthogonal methods","pmids":["38315854"],"is_preprint":false}],"current_model":"MAML2 is a transcriptional coactivator whose oncogenic activity is most extensively characterized through the CRTC1-MAML2 fusion: this chimeric protein constitutively recruits p300/CBP to CREB targets (via the MAML2 TAD1-KIX interaction) and co-activates CREB, MYC, and NOTCH/RBPJ transcriptional programs, driving salivary gland mucoepidermoid carcinoma by upregulating downstream effectors including AREG/EGFR, LINC00473/NONO, and PGC-1α4/IGF-1 circuits; YAP1-MAML2 fusions in other tumor types function through TEAD-dependent, Hippo-resistant YAP activity and phase separation-mediated selective gene activation."},"narrative":{"teleology":[{"year":2004,"claim":"Identification of the t(11;19) CRTC1-MAML2 fusion established that MAML2's Notch ICD-binding basic domain is replaced in the chimera, raising the question of whether the oncogenic mechanism operates through Notch pathway disruption or a novel gain-of-function.","evidence":"Cloning, N-terminal mutagenesis, nuclear localization studies, and Notch target gene expression analysis in MEC tumors","pmids":["14720503"],"confidence":"High","gaps":["Whether the fusion transforms through Notch pathway modulation or an independent mechanism was unresolved","No functional transformation assay was performed"]},{"year":2005,"claim":"Two independent studies converged to show that CRTC1-MAML2 transforms cells by constitutively activating CREB-dependent transcription via p300/CBP recruitment, not through Notch target gene activation, resolving the central mechanistic question.","evidence":"Co-immunoprecipitation, dominant-negative CREB blocking, in-frame deletion mutagenesis of CREB-binding domain, transformation assays, and genome-wide gene expression profiling across multiple cell lines","pmids":["15961999","16103063"],"confidence":"High","gaps":["The structural basis for MAML2-mediated CBP/p300 recruitment was unknown","Downstream CREB target genes mediating transformation were not identified"]},{"year":2006,"claim":"RNAi knockdown with rescue demonstrated that sustained CRTC1-MAML2 expression is required for MEC cell growth, establishing oncogene addiction and validating the fusion as a therapeutic target.","evidence":"RNAi knockdown, colony formation assay, in vivo xenograft, rescue with siRNA-resistant mutant construct","pmids":["16652146"],"confidence":"High","gaps":["No in vivo genetic model existed to prove the fusion is sufficient for tumor initiation","Specific downstream effectors mediating growth dependence were unknown"]},{"year":2013,"claim":"Identification of AREG as a direct CRTC1-MAML2/CREB transcriptional target that activates autocrine EGFR signaling revealed a druggable downstream effector pathway.","evidence":"RNAi, gene expression analysis, pharmacological EGFR inhibition, in vitro and in vivo xenograft models","pmids":["23975434"],"confidence":"High","gaps":["Whether EGFR inhibition alone is sufficient for durable tumor regression was untested","Additional CREB target genes contributing to transformation remained uncharacterized"]},{"year":2014,"claim":"Discovery that CRTC1-MAML2 physically interacts with MYC and activates MYC transcriptional targets revealed a gain-of-function activity beyond CREB, expanding the oncogenic mechanism.","evidence":"Reciprocal co-immunoprecipitation, gene expression profiling, transformation assays with loss-of-interaction mutants in MEC cells","pmids":["25071166"],"confidence":"High","gaps":["The domain on MAML2 mediating MYC interaction was not mapped","Relative contribution of MYC vs. CREB axis to in vivo tumorigenesis was unclear"]},{"year":2015,"claim":"Structural characterization of the MAML2 TAD1-KIX domain interaction provided the molecular basis for constitutive CBP/p300 recruitment, showing that a conserved ~20-residue segment forms an alpha-helix on the MLL1-binding surface of KIX.","evidence":"In vitro peptide-KIX binding assay, NMR structural analysis, sequence conservation analysis","pmids":["26274502"],"confidence":"High","gaps":["Whether disrupting the TAD1-KIX interaction is therapeutically tractable was untested","Full-length MAML2 structural context was not determined"]},{"year":2018,"claim":"LINC00473 was identified as a top CRTC1-MAML2-induced lncRNA that binds NONO and creates a positive feedback loop amplifying CREB transcription, establishing a non-coding RNA layer in the oncogenic circuit.","evidence":"Gene expression profiling, RNAi, RNA immunoprecipitation, RNA in situ hybridization, in vivo xenograft loss-of-function","pmids":["29353885"],"confidence":"High","gaps":["How NONO binding to LINC00473 mechanistically enhances CREB transcription was not determined","Whether LINC00473 functions in fusion-negative contexts was unknown"]},{"year":2019,"claim":"Discovery of recurrent YAP1-MAML2 fusions in poromas and porocarcinomas, with TEAD reporter activation and anchorage-independent growth, established a second major MAML2 fusion class operating through Hippo/YAP signaling.","evidence":"RNA sequencing, FISH, TEAD luciferase reporter assay, anchorage-independent growth assay","pmids":["31145701"],"confidence":"High","gaps":["Whether the MAML2 portion contributes transcriptional activation function or merely stabilizes YAP was unknown","No in vivo tumor model existed for YAP1-MAML2"]},{"year":2021,"claim":"A conditional transgenic mouse model demonstrated that CRTC1-MAML2 expression is sufficient for MEC formation with 100% penetrance, and cooperating p16-CDK4/6-RB pathway alterations were identified, enabling rational combination therapy (erlotinib plus palbociclib).","evidence":"Cre-conditional transgenic mouse, inducible RNAi in xenografts, molecular pathway analysis, combination drug treatment in vitro and in vivo","pmids":["33830080"],"confidence":"High","gaps":["Cell of origin for CRTC1-MAML2-driven MEC was not definitively established","Combination therapy efficacy in human patients was not tested"]},{"year":2021,"claim":"Identification of PGC-1α4 induction and autocrine IGF-1/IGF-1R signaling as a CRTC1-MAML2-driven vulnerability revealed an additional targetable downstream axis distinct from AREG/EGFR.","evidence":"Gene expression profiling, small-molecule drug screens, knockdown studies, IGF-1R inhibitor treatment in cell lines and primary tumors","pmids":["33626346"],"confidence":"High","gaps":["Whether IGF-1R and EGFR inhibition are complementary or redundant was not resolved","The mechanism by which CRTC1-MAML2 selectively induces the PGC-1α4 isoform was unclear"]},{"year":2022,"claim":"In vivo mouse modeling showed YAP1-MAML2 drives meningioma-like tumors through Hippo-resistant TEAD-dependent YAP activity, and constitutively active YAP alone recapitulated tumorigenesis, clarifying that the MAML2 portion confers Hippo resistance rather than independent transcriptional coactivation.","evidence":"Mouse in vivo tumor induction, gene expression profiling, YAP-TEAD inhibitor treatment ex vivo, constitutively active YAP mutant expression","pmids":["36008139"],"confidence":"High","gaps":["Whether MAML2's TAD contributes any transcriptional enhancement beyond Hippo evasion was not fully resolved","In vivo therapeutic efficacy of TEAD inhibitors was not tested"]},{"year":2023,"claim":"A pathogenic MAML2 variant was linked to congenital hypothyroidism by exerting a dominant-negative effect on Notch signaling, establishing the first Mendelian disease association and revealing that MAML2's Notch coactivator function is essential for HES1-dependent thyroid hormone biosynthesis.","evidence":"Next-generation sequencing, functional assays in HEK293T and thyroid cells, zebrafish and mouse models, organoid culture, transcriptome analysis","pmids":["36898841"],"confidence":"Medium","gaps":["Single family study; independent replication in additional patients is needed","Whether other MAML family members compensate for MAML2 loss in thyroid was not addressed"]},{"year":2024,"claim":"YAP1-MAML2 undergoes phase separation forming transcriptionally active condensates, but chemogenetic dissolution showed that only a small subset of target genes (including CTGF, CYR61) require phase separation, while most targets are activated by diffuse TF complexes.","evidence":"Live imaging, FRAP, chemogenetic condensate dissolution tool, RNA-seq at matched protein levels","pmids":["38315854"],"confidence":"High","gaps":["What distinguishes genes requiring phase separation from those that do not is unknown","Whether phase separation contributes to YAP1-MAML2 in vivo tumorigenesis was not tested"]},{"year":null,"claim":"Key unresolved questions include the physiological (non-fusion) functions of wild-type MAML2 beyond Notch coactivation, the structural basis for MAML2-MYC interaction, and whether the TAD of MAML2 contributes transcriptional coactivation independently of the fusion partner in YAP1-MAML2-driven tumors.","evidence":"","pmids":[],"confidence":"Low","gaps":["Wild-type MAML2's non-Notch transcriptional roles are poorly characterized","No full-length MAML2 structure exists","Therapeutic strategies targeting MAML2 directly have not been developed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,8,14,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,11,14,15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,7,12]}],"complexes":["Notch transcription complex (RBPJ/NICD/MAML2)","CRTC1-MAML2/CREB/p300 complex"],"partners":["RBPJ","CREBBP","EP300","MYC","CREB1","NONO","TEAD1"],"other_free_text":[]},"mechanistic_narrative":"MAML2 is a transcriptional coactivator that participates in Notch/RBPJ-dependent transcription and, through recurrent chromosomal fusions, drives tumorigenesis in multiple tissue contexts. The CRTC1-MAML2 fusion, generated by t(11;19), constitutively recruits p300/CBP to CREB target genes via direct binding of MAML2's TAD1 domain to the CBP KIX domain, activating CREB-dependent transcription programs including AREG/EGFR autocrine signaling, LINC00473/NONO-mediated positive feedback, and PGC-1α4/IGF-1 circuits, and additionally co-opts MYC transcriptional activity to sustain transformation [PMID:15961999, PMID:26274502, PMID:23975434, PMID:25071166, PMID:29353885, PMID:33626346]. YAP1-MAML2 fusions drive poromas, porocarcinomas, and meningioma-like tumors through Hippo-resistant, TEAD-dependent YAP transcriptional activity, with phase separation of the fusion selectively amplifying a subset of YAP target genes [PMID:31145701, PMID:36008139, PMID:38315854]. A pathogenic MAML2 variant causes congenital hypothyroidism through dominant-negative disruption of Notch signaling and consequent loss of HES1-dependent thyroid hormone biosynthesis gene expression [PMID:36898841]."},"prefetch_data":{"uniprot":{"accession":"Q8IZL2","full_name":"Mastermind-like protein 2","aliases":[],"length_aa":1156,"mass_kda":125.2,"function":"Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Potentiates activation by NOTCH3 and NOTCH4 more efficiently than MAML1 or MAML3","subcellular_location":"Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q8IZL2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAML2","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAML2","total_profiled":1310},"omim":[{"mim_id":"608991","title":"MASTERMIND-LIKE 3; MAML3","url":"https://www.omim.org/entry/608991"},{"mim_id":"607537","title":"MASTERMIND-LIKE 2; MAML2","url":"https://www.omim.org/entry/607537"},{"mim_id":"607536","title":"CREB-REGULATED TRANSCRIPTION COACTIVATOR 1; CRTC1","url":"https://www.omim.org/entry/607536"},{"mim_id":"159555","title":"LYSINE-SPECIFIC METHYLTRANSFERASE 2A; KMT2A","url":"https://www.omim.org/entry/159555"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAML2"},"hgnc":{"alias_symbol":["KIAA1819","MAM3"],"prev_symbol":[]},"alphafold":{"accession":"Q8IZL2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZL2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZL2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZL2-F1-predicted_aligned_error_v6.png","plddt_mean":45.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAML2","jax_strain_url":"https://www.jax.org/strain/search?query=MAML2"},"sequence":{"accession":"Q8IZL2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZL2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZL2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZL2"}},"corpus_meta":[{"pmid":"20588178","id":"PMC_20588178","title":"A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas.","date":"2010","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20588178","citation_count":209,"is_preprint":false},{"pmid":"31145701","id":"PMC_31145701","title":"Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31145701","citation_count":198,"is_preprint":false},{"pmid":"16818685","id":"PMC_16818685","title":"MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/16818685","citation_count":169,"is_preprint":false},{"pmid":"17369439","id":"PMC_17369439","title":"MAM3 catalyzes the formation of all aliphatic glucosinolate chain lengths in Arabidopsis.","date":"2007","source":"Plant 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A, Pathological anatomy and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/2508309","citation_count":9,"is_preprint":false},{"pmid":"35251626","id":"PMC_35251626","title":"Establishment of a patient-derived mucoepidermoid carcinoma cell line with the CRTC1-MAML2 fusion gene.","date":"2022","source":"Molecular and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35251626","citation_count":9,"is_preprint":false},{"pmid":"37565303","id":"PMC_37565303","title":"Loss of YAP1 C-terminus expression as an ancillary marker for metaplastic thymoma: a potential pitfall in detecting YAP1::MAML2 gene rearrangement.","date":"2023","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/37565303","citation_count":9,"is_preprint":false},{"pmid":"28927048","id":"PMC_28927048","title":"Mucoepidermoid carcinoma of the sublingual gland harboring a translocation of the MAML2 gene: A case report.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28927048","citation_count":9,"is_preprint":false},{"pmid":"29169286","id":"PMC_29169286","title":"Sclerosing Mucoepidermoid Carcinoma in the Parotid Gland With CRTC1-MAML2 Fusion: A Case Report.","date":"2017","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29169286","citation_count":9,"is_preprint":false},{"pmid":"36357765","id":"PMC_36357765","title":"Diagnostic Reliability of CRTC1/3::MAML2 Gene Fusion Transcripts in Discriminating Histologically Similar Intraosseous Mucoepidermoid Carcinoma from Glandular Odontogenic Cyst: A Systematic Review and Meta-analysis.","date":"2022","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36357765","citation_count":8,"is_preprint":false},{"pmid":"37628996","id":"PMC_37628996","title":"Atypical Intraparenchymal Meningioma with YAP1-MAML2 Fusion in a Young Adult Male: A Case Report and Mini Literature Review.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37628996","citation_count":8,"is_preprint":false},{"pmid":"36898841","id":"PMC_36898841","title":"Pathogenic variations in MAML2 and MAMLD1 contribute to congenital hypothyroidism due to dyshormonogenesis by regulating the Notch signalling pathway.","date":"2023","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36898841","citation_count":6,"is_preprint":false},{"pmid":"38304779","id":"PMC_38304779","title":"MAML2 gene rearrangement occurs in all Warthin-like mucoepidermoid carcinoma: A reappraisal in a series of 29 cases.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38304779","citation_count":6,"is_preprint":false},{"pmid":"36463108","id":"PMC_36463108","title":"Pediatric meningioma with a Novel MAML2-YAP1 fusion variant: a case report and literature review.","date":"2022","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/36463108","citation_count":6,"is_preprint":false},{"pmid":"1917564","id":"PMC_1917564","title":"Immunohistochemical distribution of MAM-3 and MAM-6 antigens in developing salivary glands of the human fetus.","date":"1991","source":"The Histochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/1917564","citation_count":6,"is_preprint":false},{"pmid":"1849991","id":"PMC_1849991","title":"Immunohistochemical localization of MAM-3 and MAM-6 antigens in adenoid cystic carcinoma.","date":"1991","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/1849991","citation_count":6,"is_preprint":false},{"pmid":"35986430","id":"PMC_35986430","title":"YAP1-MAML2 fusion in a pediatric NF2-wildtype intraparenchymal brainstem schwannoma.","date":"2022","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/35986430","citation_count":6,"is_preprint":false},{"pmid":"37284641","id":"PMC_37284641","title":"The Multifaceted Appearance of Supratentorial Ependymoma with ZFTA-MAML2 Fusion.","date":"2021","source":"Free neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/37284641","citation_count":5,"is_preprint":false},{"pmid":"31343482","id":"PMC_31343482","title":"Inv(11)(q21q23); KMT2A-MAML2, a Recurrent Genetic Abnormality in T-Cell Therapy-related Acute Lymphoblastic Leukemia.","date":"2020","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31343482","citation_count":5,"is_preprint":false},{"pmid":"31954088","id":"PMC_31954088","title":"Ameloblastoma with mucous cells: A clinicopathological, BRAF mutation, and MAML2 rearrangement study.","date":"2020","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31954088","citation_count":4,"is_preprint":false},{"pmid":"30605061","id":"PMC_30605061","title":"Gefitinib Represses JAK-STAT Signaling Activated by CRTC1-MAML2 Fusion in Mucoepidermoid Carcinoma Cells.","date":"2019","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/30605061","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52946,"output_tokens":4985,"usd":0.116806},"stage2":{"model":"claude-opus-4-6","input_tokens":8472,"output_tokens":3486,"usd":0.194265},"total_usd":0.311071,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"The t(11;19) translocation creates a WAMTP1-MAML2 (later called CRTC1-MAML2) fusion protein in which the N-terminal basic domain of MAML2 required for binding to intracellular Notch (Notch ICD) is replaced by an unrelated N-terminal sequence from WAMTP1. Mutation analysis identified two regions important for nuclear localization (amino acids 11-20) and colocalization with MAML2 and Notch1 ICD in nuclear granules (amino acids 21-42). The fusion results in upregulation of HES5 and downregulation of MASH1 in fusion-positive MECs, indicating altered Notch signaling.\",\n      \"method\": \"Cloning, mutation analysis of N-terminus, nuclear localization studies, Notch target gene expression analysis in MEC tumors\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mutagenesis, localization, target gene expression) in a single study\",\n      \"pmids\": [\"14720503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The MECT1-MAML2 fusion protein binds to CREB, recruits p300/CBP into the CREB complex through a binding domain on MAML2, and constitutively activates CREB-dependent transcription. Blocking CREB DNA binding markedly reduced the transforming activity of MECT1-MAML2, demonstrating that constitutive CREB activation is the primary mechanism of transformation.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays, dominant-negative CREB blocking, gene expression analysis, transformation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including binding assays, mutagenesis of CREB-binding activity, and functional transformation readout\",\n      \"pmids\": [\"15961999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Small in-frame deletions within the CREB-binding domain of Mect1/Torc1 portion of the Mect1-Maml2 fusion completely abolished transforming activity in RK3E epithelial cells. Ectopic induction of Mect1-Maml2 strongly activated known cAMP/CREB-regulated genes but did not alter known Notch-regulated target genes, establishing that cAMP/CREB pathway activation (not Notch signaling) is the primary oncogenic mechanism.\",\n      \"method\": \"In-frame deletion mutagenesis, doxycycline-regulated expression, global gene expression profiling, RT-PCR validation in multiple cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus gene expression profiling with validation across multiple cell lines, replicated key finding from Wu et al. 2005\",\n      \"pmids\": [\"16103063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sustained expression of Mect1-Maml2 is required for tumor cell growth in MEC cancer cells carrying the t(11;19) translocation. RNAi-mediated knockdown of the fusion peptide caused at least 90% colony growth inhibition in MEC cell lines, while having no effect on non-MEC tumors. A rescue experiment using a mutant Mect1-Maml2 with silent changes in the RNAi target sequence partially restored growth, confirming on-target specificity.\",\n      \"method\": \"RNAi knockdown, colony formation assay, in vivo xenograft, rescue experiment with RNAi-resistant mutant\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi plus rescue experiment with multiple cell lines and in vivo validation\",\n      \"pmids\": [\"16652146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The CRTC1-MAML2 gene fusion is present in 50% of clear cell hidradenomas (benign skin tumors), demonstrating that the fusion's oncogenic activity extends beyond salivary and bronchial gland tumors. All fusion-positive hidradenomas had clear cell morphology, while all fusion-negative tumors lacked clear cells, establishing a genotype-phenotype correlation.\",\n      \"method\": \"FISH, RT-PCR, immunohistochemistry\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — detection methods without direct mechanistic functional assays, but clear genotype-phenotype correlation\",\n      \"pmids\": [\"17334997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A novel MLL-MAML2 fusion gene is created by inv(11)(q21q23) in secondary AML/MDS. In the fusion, the N-terminal basic domain of MAML2 (including the Notch ICD binding site) is deleted. Luciferase assay demonstrated that MLL-MAML2 suppresses HES1 promoter activation by NOTCH1 intracellular domain, indicating dominant-negative disruption of Notch signaling.\",\n      \"method\": \"RT-PCR, sequencing, luciferase reporter assay for HES1 promoter\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional luciferase assay demonstrating mechanistic effect on Notch target, single lab\",\n      \"pmids\": [\"17551948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRTC1-MAML2 fusion oncogene is required for growth and survival of fusion-positive MEC cells in vitro and in vivo. The oncoprotein induces upregulation of the EGFR ligand Amphiregulin (AREG) by co-activating transcription factor CREB, and AREG subsequently activates EGFR signaling in an autocrine manner. CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition.\",\n      \"method\": \"RNA interference, gene expression analysis, pharmacological EGFR inhibition, in vitro growth assays, in vivo xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNAi, pharmacological inhibition, in vitro and in vivo) establishing the CRTC1-MAML2→CREB→AREG→EGFR axis\",\n      \"pmids\": [\"23975434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The CRTC1/MAML2 (C1/M2) oncoprotein interacts with MYC proteins and activates MYC transcription targets including genes involved in cell growth, metabolism, survival, and tumorigenesis. The C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation, representing a gain-of-function activity beyond CREB and NOTCH pathway dysregulation.\",\n      \"method\": \"Co-immunoprecipitation, gene expression profiling, transformation assays in human MEC tumor cells with t(11;19)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional transformation assay with loss-of-interaction validation\",\n      \"pmids\": [\"25071166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A peptide derived from transactivation domain 1 (TAD1) of MAML2 binds directly to the CBP KIX domain with micromolar affinity. An ~20-residue segment within this peptide, conserved in MAML2 orthologs and paralogs, binds a KIX surface previously shown to bind MLL1, forming an alpha-helix similar to the MLL1-KIX interaction. Because CRTC1/3-MAML2 fusion proteins are constitutively nuclear, this provides the mechanism for constitutive CBP/p300 recruitment to CREB targets.\",\n      \"method\": \"In vitro binding assay (peptide-KIX domain), NMR structural analysis, sequence conservation analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted binding with structural characterization of the MAML2 TAD1-KIX interface\",\n      \"pmids\": [\"26274502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Stilbenoids (resveratrol and pterostilbene) induce de novo methylation at the MAML2 enhancer, recruiting DNMT3B and reducing OCT1 transcription factor occupancy, leading to transcriptional silencing of MAML2 and downregulation of NOTCH target genes in breast cancer cells. Increased repressive histone marks and decreased activating marks accompany the enhanced DNA methylation.\",\n      \"method\": \"Genome-wide DNA methylation analysis (Illumina 450K), ChIP assay, immunohistochemistry, transcriptomics\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and methylation analysis with functional gene expression consequence, single lab\",\n      \"pmids\": [\"27207652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRTC1-MAML2 fusion induces transcription of the lncRNA LINC00473, which was the top downregulated target upon CRTC1-MAML2 depletion. LINC00473 induction requires CRTC1-MAML2's ability to activate CREB-mediated transcription. LINC00473 localizes predominantly to the nucleus and binds the cAMP signaling component NONO, enhancing CRTC1-MAML2-mediated CREB transcription in a positive feedback loop. LINC00473 depletion reduced MEC cell proliferation and blocked in vivo tumor growth.\",\n      \"method\": \"Gene expression profiling, RNA interference, RIP assay, RNA in situ hybridization, in vivo xenograft, loss-of-function studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, RNAi, in vitro and in vivo) establishing LINC00473 as a CRTC1-MAML2 downstream mediator\",\n      \"pmids\": [\"29353885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1-MAML2 fusions are highly recurrent in poromas (88.5%) and porocarcinomas (63.6%). The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic role through YAP/TEAD-dependent transcription.\",\n      \"method\": \"RNA sequencing, RT-PCR, FISH, TEAD reporter luciferase assay, anchorage-independent growth assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional TEAD reporter assay plus transformation assay, multiple orthogonal detection methods\",\n      \"pmids\": [\"31145701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTC1-MAML2 is the major oncogenic driver of MEC in vivo: doxycycline-induced CRTC1-MAML2 knockdown blocked established MEC xenograft growth, and Cre-induced CRTC1-MAML2 expression in a conditional transgenic mouse model caused 100% penetrant salivary gland tumor formation resembling human MEC. Altered p16-CDK4/6-RB pathway activity was identified as a cooperating event, and cotargeting AREG/EGFR (erlotinib) and CDK4/6 (palbociclib) produced enhanced antitumor responses.\",\n      \"method\": \"Inducible RNAi knockdown in xenografts, conditional transgenic mouse model, molecular pathway analysis, combination drug treatment in vitro and in vivo\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — conditional transgenic model with 100% penetrance plus xenograft rescue, multiple orthogonal methods establishing CRTC1-MAML2 as causal driver\",\n      \"pmids\": [\"33830080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTC1/MAML2 (C1/M2) induces transcriptional activation of the non-canonical PGC-1α splice variant PGC-1α4, which drives PPARγ-mediated IGF-1 expression in an autocrine circuit. C1/M2-positive MEC cells are selectively sensitive to IGF-1R inhibition and PPARγ inverse agonists, revealing a PGC-1α-IGF-1 signaling axis as a vulnerability in fusion-positive tumors.\",\n      \"method\": \"Gene expression profiling, small-molecule drug screens, knockdown studies, IGF-1R inhibitor treatment in cell lines and primary tumors\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (transcriptomics, pharmacological, genetic) across cell lines and primary tumors\",\n      \"pmids\": [\"33626346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LINC01152 positively regulates MAML2 in GBM cells by sponging miR-466 and by recruiting SRSF1. In turn, the RBPJ/MAML2 transcription complex activates transcription of LINC01152, forming a positive feedback loop that promotes GBM tumorigenesis via the Notch signaling pathway.\",\n      \"method\": \"RNA pulldown assay, luciferase reporter assay, RIP assay, ChIP assay, functional proliferation/apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding assays (pulldown, RIP, ChIP) plus functional readouts, single lab\",\n      \"pmids\": [\"33483471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Expression of YAP1-MAML2 in mice induces meningioma-like tumors resembling NF2 mutant meningiomas by gene expression. Treatment with YAP-TEAD inhibitors is sufficient to inhibit viability of YAP1-MAML2-driven mouse tumors ex vivo. Constitutively active YAP1 (S127/397A-YAP1) alone is sufficient to induce similar tumors, establishing that the YAP component drives oncogenesis.\",\n      \"method\": \"Mouse in vivo tumor induction, gene expression profiling, YAP-TEAD inhibitor treatment ex vivo, constitutively active YAP1 mutant expression\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo mouse model plus pharmacological TEAD inhibition and active-site mutant validation, multiple orthogonal approaches\",\n      \"pmids\": [\"36008139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A pathogenic MAML2 variant was identified in a patient with congenital hypothyroidism due to dyshormonogenesis. The MAML2 variant exerted a dominant-negative effect on canonical Notch signaling and on thyroid hormone biosynthesis. In zebrafish and mouse models, Notch pathway inhibition (γ-secretase inhibitor) recapitulated hypothyroidism and dyshormonogenesis. HES1, a Notch target transactivated by MAML2, directly regulates thyroid hormone biosynthesis gene expression.\",\n      \"method\": \"Next-generation sequencing, in vitro functional assays in HEK293T and Nthy-ori 3.1 cells, zebrafish and mouse models, organoid culture, transcriptome sequencing\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems and functional assays, single lab, dominant-negative mechanism validated in vitro and in vivo\",\n      \"pmids\": [\"36898841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YAP1-MAML2 undergoes phase separation and forms liquid-like condensates bearing hallmarks of transcriptional activity. Using a chemogenetic tool to dissolve TF condensates, phase separation was found to further upregulate a small fraction of YAP1-MAML2-regulated genes (including canonical YAP targets CTGF and CYR61) while the majority of YAP1-MAML2-regulated genes are not affected by phase separation, indicating that diffuse TF complexes can activate transcription without phase separation.\",\n      \"method\": \"Phase separation assays (live imaging, FRAP), chemogenetic dissolution of condensates, RNA-seq comparison of phase-separated vs. non-phase-separated conditions at identical protein levels\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct live imaging, FRAP, and chemogenetic tool with transcriptome-wide readout, multiple orthogonal methods\",\n      \"pmids\": [\"38315854\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAML2 is a transcriptional coactivator whose oncogenic activity is most extensively characterized through the CRTC1-MAML2 fusion: this chimeric protein constitutively recruits p300/CBP to CREB targets (via the MAML2 TAD1-KIX interaction) and co-activates CREB, MYC, and NOTCH/RBPJ transcriptional programs, driving salivary gland mucoepidermoid carcinoma by upregulating downstream effectors including AREG/EGFR, LINC00473/NONO, and PGC-1α4/IGF-1 circuits; YAP1-MAML2 fusions in other tumor types function through TEAD-dependent, Hippo-resistant YAP activity and phase separation-mediated selective gene activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAML2 is a transcriptional coactivator that participates in Notch/RBPJ-dependent transcription and, through recurrent chromosomal fusions, drives tumorigenesis in multiple tissue contexts. The CRTC1-MAML2 fusion, generated by t(11;19), constitutively recruits p300/CBP to CREB target genes via direct binding of MAML2's TAD1 domain to the CBP KIX domain, activating CREB-dependent transcription programs including AREG/EGFR autocrine signaling, LINC00473/NONO-mediated positive feedback, and PGC-1α4/IGF-1 circuits, and additionally co-opts MYC transcriptional activity to sustain transformation [PMID:15961999, PMID:26274502, PMID:23975434, PMID:25071166, PMID:29353885, PMID:33626346]. YAP1-MAML2 fusions drive poromas, porocarcinomas, and meningioma-like tumors through Hippo-resistant, TEAD-dependent YAP transcriptional activity, with phase separation of the fusion selectively amplifying a subset of YAP target genes [PMID:31145701, PMID:36008139, PMID:38315854]. A pathogenic MAML2 variant causes congenital hypothyroidism through dominant-negative disruption of Notch signaling and consequent loss of HES1-dependent thyroid hormone biosynthesis gene expression [PMID:36898841].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of the t(11;19) CRTC1-MAML2 fusion established that MAML2's Notch ICD-binding basic domain is replaced in the chimera, raising the question of whether the oncogenic mechanism operates through Notch pathway disruption or a novel gain-of-function.\",\n      \"evidence\": \"Cloning, N-terminal mutagenesis, nuclear localization studies, and Notch target gene expression analysis in MEC tumors\",\n      \"pmids\": [\"14720503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the fusion transforms through Notch pathway modulation or an independent mechanism was unresolved\",\n        \"No functional transformation assay was performed\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Two independent studies converged to show that CRTC1-MAML2 transforms cells by constitutively activating CREB-dependent transcription via p300/CBP recruitment, not through Notch target gene activation, resolving the central mechanistic question.\",\n      \"evidence\": \"Co-immunoprecipitation, dominant-negative CREB blocking, in-frame deletion mutagenesis of CREB-binding domain, transformation assays, and genome-wide gene expression profiling across multiple cell lines\",\n      \"pmids\": [\"15961999\", \"16103063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis for MAML2-mediated CBP/p300 recruitment was unknown\",\n        \"Downstream CREB target genes mediating transformation were not identified\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"RNAi knockdown with rescue demonstrated that sustained CRTC1-MAML2 expression is required for MEC cell growth, establishing oncogene addiction and validating the fusion as a therapeutic target.\",\n      \"evidence\": \"RNAi knockdown, colony formation assay, in vivo xenograft, rescue with siRNA-resistant mutant construct\",\n      \"pmids\": [\"16652146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo genetic model existed to prove the fusion is sufficient for tumor initiation\",\n        \"Specific downstream effectors mediating growth dependence were unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of AREG as a direct CRTC1-MAML2/CREB transcriptional target that activates autocrine EGFR signaling revealed a druggable downstream effector pathway.\",\n      \"evidence\": \"RNAi, gene expression analysis, pharmacological EGFR inhibition, in vitro and in vivo xenograft models\",\n      \"pmids\": [\"23975434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether EGFR inhibition alone is sufficient for durable tumor regression was untested\",\n        \"Additional CREB target genes contributing to transformation remained uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that CRTC1-MAML2 physically interacts with MYC and activates MYC transcriptional targets revealed a gain-of-function activity beyond CREB, expanding the oncogenic mechanism.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, gene expression profiling, transformation assays with loss-of-interaction mutants in MEC cells\",\n      \"pmids\": [\"25071166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The domain on MAML2 mediating MYC interaction was not mapped\",\n        \"Relative contribution of MYC vs. CREB axis to in vivo tumorigenesis was unclear\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Structural characterization of the MAML2 TAD1-KIX domain interaction provided the molecular basis for constitutive CBP/p300 recruitment, showing that a conserved ~20-residue segment forms an alpha-helix on the MLL1-binding surface of KIX.\",\n      \"evidence\": \"In vitro peptide-KIX binding assay, NMR structural analysis, sequence conservation analysis\",\n      \"pmids\": [\"26274502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether disrupting the TAD1-KIX interaction is therapeutically tractable was untested\",\n        \"Full-length MAML2 structural context was not determined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"LINC00473 was identified as a top CRTC1-MAML2-induced lncRNA that binds NONO and creates a positive feedback loop amplifying CREB transcription, establishing a non-coding RNA layer in the oncogenic circuit.\",\n      \"evidence\": \"Gene expression profiling, RNAi, RNA immunoprecipitation, RNA in situ hybridization, in vivo xenograft loss-of-function\",\n      \"pmids\": [\"29353885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How NONO binding to LINC00473 mechanistically enhances CREB transcription was not determined\",\n        \"Whether LINC00473 functions in fusion-negative contexts was unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery of recurrent YAP1-MAML2 fusions in poromas and porocarcinomas, with TEAD reporter activation and anchorage-independent growth, established a second major MAML2 fusion class operating through Hippo/YAP signaling.\",\n      \"evidence\": \"RNA sequencing, FISH, TEAD luciferase reporter assay, anchorage-independent growth assay\",\n      \"pmids\": [\"31145701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the MAML2 portion contributes transcriptional activation function or merely stabilizes YAP was unknown\",\n        \"No in vivo tumor model existed for YAP1-MAML2\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A conditional transgenic mouse model demonstrated that CRTC1-MAML2 expression is sufficient for MEC formation with 100% penetrance, and cooperating p16-CDK4/6-RB pathway alterations were identified, enabling rational combination therapy (erlotinib plus palbociclib).\",\n      \"evidence\": \"Cre-conditional transgenic mouse, inducible RNAi in xenografts, molecular pathway analysis, combination drug treatment in vitro and in vivo\",\n      \"pmids\": [\"33830080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell of origin for CRTC1-MAML2-driven MEC was not definitively established\",\n        \"Combination therapy efficacy in human patients was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of PGC-1α4 induction and autocrine IGF-1/IGF-1R signaling as a CRTC1-MAML2-driven vulnerability revealed an additional targetable downstream axis distinct from AREG/EGFR.\",\n      \"evidence\": \"Gene expression profiling, small-molecule drug screens, knockdown studies, IGF-1R inhibitor treatment in cell lines and primary tumors\",\n      \"pmids\": [\"33626346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IGF-1R and EGFR inhibition are complementary or redundant was not resolved\",\n        \"The mechanism by which CRTC1-MAML2 selectively induces the PGC-1α4 isoform was unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In vivo mouse modeling showed YAP1-MAML2 drives meningioma-like tumors through Hippo-resistant TEAD-dependent YAP activity, and constitutively active YAP alone recapitulated tumorigenesis, clarifying that the MAML2 portion confers Hippo resistance rather than independent transcriptional coactivation.\",\n      \"evidence\": \"Mouse in vivo tumor induction, gene expression profiling, YAP-TEAD inhibitor treatment ex vivo, constitutively active YAP mutant expression\",\n      \"pmids\": [\"36008139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MAML2's TAD contributes any transcriptional enhancement beyond Hippo evasion was not fully resolved\",\n        \"In vivo therapeutic efficacy of TEAD inhibitors was not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A pathogenic MAML2 variant was linked to congenital hypothyroidism by exerting a dominant-negative effect on Notch signaling, establishing the first Mendelian disease association and revealing that MAML2's Notch coactivator function is essential for HES1-dependent thyroid hormone biosynthesis.\",\n      \"evidence\": \"Next-generation sequencing, functional assays in HEK293T and thyroid cells, zebrafish and mouse models, organoid culture, transcriptome analysis\",\n      \"pmids\": [\"36898841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single family study; independent replication in additional patients is needed\",\n        \"Whether other MAML family members compensate for MAML2 loss in thyroid was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"YAP1-MAML2 undergoes phase separation forming transcriptionally active condensates, but chemogenetic dissolution showed that only a small subset of target genes (including CTGF, CYR61) require phase separation, while most targets are activated by diffuse TF complexes.\",\n      \"evidence\": \"Live imaging, FRAP, chemogenetic condensate dissolution tool, RNA-seq at matched protein levels\",\n      \"pmids\": [\"38315854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"What distinguishes genes requiring phase separation from those that do not is unknown\",\n        \"Whether phase separation contributes to YAP1-MAML2 in vivo tumorigenesis was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the physiological (non-fusion) functions of wild-type MAML2 beyond Notch coactivation, the structural basis for MAML2-MYC interaction, and whether the TAD of MAML2 contributes transcriptional coactivation independently of the fusion partner in YAP1-MAML2-driven tumors.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Wild-type MAML2's non-Notch transcriptional roles are poorly characterized\",\n        \"No full-length MAML2 structure exists\",\n        \"Therapeutic strategies targeting MAML2 directly have not been developed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 8, 14, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [1, 2, 6, 10, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 11, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 7, 12]}\n    ],\n    \"complexes\": [\n      \"Notch transcription complex (RBPJ/NICD/MAML2)\",\n      \"CRTC1-MAML2/CREB/p300 complex\"\n    ],\n    \"partners\": [\n      \"RBPJ\",\n      \"CREBBP\",\n      \"EP300\",\n      \"MYC\",\n      \"CREB1\",\n      \"NONO\",\n      \"TEAD1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}