{"gene":"MAML2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2005,"finding":"The MECT1-MAML2 (CRTC1-MAML2) fusion protein binds to CREB and recruits p300/CBP into the CREB transcriptional complex through a binding domain on the MAML2 portion, constitutively activating CREB-dependent transcription and inducing expression of multiple CREB target genes. The transforming activity of MECT1-MAML2 was markedly reduced by blocking CREB DNA binding.","method":"Co-immunoprecipitation, reporter assays, gene expression analysis, dominant-negative CREB blocking, transformation assays in epithelial cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, functional mutagenesis (CREB-blocking), transformation assay, and gene expression profiling in a single rigorous study; replicated by independent lab (PMID:16103063)","pmids":["15961999"],"is_preprint":false},{"year":2005,"finding":"The transforming activity of the MECT1-MAML2 fusion oncogene depends on an intact CREB-binding domain derived from the MECT1/TORC1 N-terminus; small in-frame deletions within this CREB-binding domain completely abolished transforming activity in RK3E epithelial cells. The fusion strongly activated cAMP/CREB-regulated genes but did not alter known Notch-regulated target genes in expression profiling experiments.","method":"In-frame deletion mutagenesis of the CREB-binding domain, transformation assay in RK3E cells, doxycycline-regulated expression system, global gene expression profiling, RT-PCR validation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with functional rescue, complemented by genome-wide expression profiling, validated in multiple cell lines including endogenous-fusion-expressing MEC cells; consistent with PMID:15961999","pmids":["16103063"],"is_preprint":false},{"year":2006,"finding":"Sustained expression of the MECT1-MAML2 fusion is required for tumor cell growth: RNAi-mediated knockdown of the fusion peptide caused ≥90% colony growth inhibition in MEC tumor cell lines carrying the t(11;19) rearrangement. Re-expression of an RNAi-resistant mutant MECT1-MAML2 partially rescued growth inhibition, confirming on-target specificity.","method":"Hairpin RNAi knockdown, colony formation assay, rescue experiment with RNAi-resistant mutant, in vivo xenograft in nude mice","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined cellular phenotype, genetic rescue control, confirmed in vivo; multiple orthogonal methods in one study","pmids":["16652146"],"is_preprint":false},{"year":2004,"finding":"The WAMTP1(CRTC1)-MAML2 fusion protein loses the N-terminal basic domain of MAML2 required for binding to intracellular Notch (Notch ICD). Mutation analysis identified two regions in the WAMTP1 N-terminus important for nuclear localization (amino acids 11-20) and for co-localization with MAML2 and Notch1 ICD in nuclear granules (amino acids 21-42). Analysis of Notch target genes in fusion-positive vs. negative MEC tumors showed upregulation of HES5 and downregulation of MASH1, indicating altered Notch signaling.","method":"Fusion gene cloning, domain deletion/mutation analysis, immunofluorescence co-localization, Notch target gene expression analysis in primary tumor samples","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mutation analysis with co-localization readout and gene expression in primary tumors, single lab","pmids":["14720503"],"is_preprint":false},{"year":2013,"finding":"The CRTC1-MAML2 fusion oncoprotein co-activates CREB transcription factor to induce upregulation of the EGFR ligand Amphiregulin (AREG), which then activates EGFR signaling in an autocrine manner promoting MEC cell growth and survival. CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition in vitro and in vivo.","method":"Gene expression analysis, RNA interference knockdown of CRTC1-MAML2, pharmacological EGFR inhibition, human MEC xenograft models in vivo","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockdown with defined downstream pathway, pharmacological validation, in vivo xenograft confirmation; replicated in subsequent studies (PMID:33830080, PMID:35251626)","pmids":["23975434"],"is_preprint":false},{"year":2014,"finding":"The CRTC1-MAML2 (C1/M2) oncoprotein interacts with MYC proteins and activates MYC transcription targets involved in cell growth, metabolism, survival, and tumorigenesis. This gain-of-function interaction with MYC is necessary for C1/M2-driven cell transformation.","method":"Co-immunoprecipitation of C1/M2 with MYC, gene expression profiling, transformation assay, validation in human MEC tumor cells harboring the t(11;19) translocation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of fusion with MYC plus transformation assay, validated in endogenous-fusion MEC cells, single lab","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 TAD1, conserved in MAML2 orthologs and paralogs, contacts a KIX surface previously shown to bind MLL1, sharing sequence and structural similarity with MLL1 at those contact positions. This provides the molecular basis for constitutive CBP/p300 recruitment by CRTC1/3-MAML2 fusion proteins.","method":"In vitro peptide binding assay (NMR/biochemical), sequence and structural analysis of KIX-binding interface","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assay with structural analysis, single lab, no mutagenesis validation of the interface in a cellular context","pmids":["26274502"],"is_preprint":false},{"year":2021,"finding":"CRTC1-MAML2 is a causal oncogenic driver for MEC: doxycycline-induced knockdown blocked growth of established MEC xenografts; conditional transgenic Cre-induced CRTC1-MAML2 expression caused 100% penetrant salivary gland tumor formation in mice resembling human MEC histologically and molecularly. Molecular analysis revealed altered p16-CDK4/6-RB pathway activity as a cooperating event; co-targeting AREG/EGFR signaling (Erlotinib) and CDK4/6 (Palbociclib) produced enhanced anti-tumor responses in vitro and in vivo.","method":"Doxycycline-inducible shRNA knockdown in xenografts, conditional transgenic mouse model (Cre-induced expression), molecular pathway analysis, pharmacological combination therapy in vitro and in vivo","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional transgenic model with 100% penetrance, loss-of-function in xenografts, multiple orthogonal methods; definitive causal driver evidence","pmids":["33830080"],"is_preprint":false},{"year":2021,"finding":"CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1α splice variant PGC-1α4, which regulates PPARγ-mediated IGF-1 expression, creating an autocrine mitogenic circuit. C1/M2-positive tumor cells are selectively sensitive to IGF-1R inhibition and to PPARγ inverse agonists.","method":"Gene expression profiling, small-molecule drug screens, knockdown/overexpression of pathway components, pharmacological inhibition of IGF-1R and PPARγ in MEC cell lines and primary tumors","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression profiling plus pharmacological validation, single lab, consistent across cell lines and primary tumors","pmids":["33626346"],"is_preprint":false},{"year":2018,"finding":"CRTC1-MAML2 fusion-induced transcription of LINC00473 (a lncRNA) is dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. LINC00473 depletion reduced MEC cell proliferation and survival in vitro and blocked tumor growth in xenografts. LINC00473 binds the cAMP signaling component NONO, enhancing CRTC1-MAML2-driven CREB-mediated transcription.","method":"Gene expression profiling, siRNA knockdown, in vivo xenograft, RNA in situ hybridization, RNA pull-down assay for NONO binding","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with in vivo confirmation plus RNA pulldown for binding partner, single lab","pmids":["29353885"],"is_preprint":false},{"year":2007,"finding":"The MLL-MAML2 fusion, created by inv(11)(q21q23), encodes a chimeric protein in which the N-terminal basic domain of MAML2 (required for binding Notch ICD) is deleted. Luciferase assay demonstrated that MLL-MAML2 suppresses HES1 promoter activation by the NOTCH1 intracellular domain, indicating disruption of Notch signaling.","method":"RT-PCR and sequencing of fusion breakpoints, luciferase reporter assay for NOTCH1-ICD-driven HES1 promoter activity","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter assay showing dominant-negative effect on Notch target, single lab, limited functional follow-up","pmids":["17551948"],"is_preprint":false},{"year":2019,"finding":"YAP1-MAML2 fusion proteins (identified by RNA-seq in poromas and porocarcinomas) strongly transactivate a TEAD reporter and promote anchorage-independent growth, confirming tumorigenic activity driven by YAP1/TEAD-dependent transcription. The YAP1 N-terminus (retained in the fusion) directs nuclear localization detectable by immunohistochemistry, while the YAP1 C-terminus is lost.","method":"RNA sequencing, RT-PCR, FISH confirmation of genomic rearrangements, TEAD luciferase reporter assay, anchorage-independent growth assay, immunohistochemistry","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reporter assay, functional transformation assay, genomic confirmation by multiple methods, replicated across 104 tumor samples; replicated in subsequent studies (PMID:36008139, PMID:38315854)","pmids":["31145701"],"is_preprint":false},{"year":2022,"finding":"YAP1-MAML2 fusion primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Expression of YAP1-MAML2 in mice induces meningioma-like tumors; constitutively active YAP1 (S127/397A) induces similar tumors, indicating that the YAP component is the critical oncogenic driver. Treatment with YAP-TEAD inhibitors inhibited viability of YAP1-MAML2-driven mouse tumors ex vivo.","method":"In vivo mouse expression model, gene expression profiling comparing YAP1 fusion-positive vs NF2 mutant meningiomas, YAP-TEAD inhibitor treatment ex vivo, constitutively active YAP1 mutagenesis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse tumor model, mutagenesis to separate YAP vs MAML2 contributions, pharmacological validation, multiple orthogonal methods","pmids":["36008139"],"is_preprint":false},{"year":2024,"finding":"YAP1-MAML2 fusion undergoes phase separation (PS) and forms liquid-like condensates with hallmarks of transcriptional activity. Using a chemogenetic tool to dissolve condensates at identical protein levels, PS was found to selectively further amplify expression of a small fraction of YAP1-MAML2 target genes (including CTGF and CYR61), while the majority of YAP1-MAML2-regulated genes are not affected by PS and can be activated by diffuse TF complexes.","method":"Live-cell phase separation imaging, chemogenetic condensate dissolution tool, comparative transcriptome analysis under phase-separated vs. non-phase-separated conditions","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemogenetic tool with paired transcriptomic readout provides mechanistic resolution, single lab, novel method","pmids":["38315854"],"is_preprint":false},{"year":2016,"finding":"Stilbenoids (resveratrol and pterostilbene) induce de novo methylation at the MAML2 enhancer region, leading to transcriptional silencing of MAML2. This coincides with increased occupancy of repressive histone marks, decreased activating marks, binding of DNMT3B, and decreased occupancy of OCT1 transcription factor at the MAML2 enhancer, resulting in downregulation of NOTCH target genes in breast cancer cells.","method":"Genome-wide Illumina 450K DNA methylation array, ChIP for histone marks and DNMT3B/OCT1, gene expression analysis","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal epigenomic methods identifying DNMT3B as writer and OCT1 as displaced reader at MAML2 enhancer, single lab","pmids":["27207652"],"is_preprint":false},{"year":2023,"finding":"A pathogenic MAML2 variant identified in a patient with congenital hypothyroidism exerts a dominant-negative effect on canonical Notch signaling and on thyroid hormone biosynthesis gene expression. In vitro functional assays in HEK293T and thyroid cells, organoid culture, and zebrafish/mouse models showed that Notch signaling within thyroid cells directly affects thyroid hormone biosynthesis; the MAML2 variant blocked HES1-dependent hormone biosynthesis gene expression.","method":"NGS variant identification, in vitro reporter/functional assays in HEK293T and Nthy-ori 3.1 cells, primary mouse thyroid organoid culture with transcriptome sequencing, zebrafish and mouse Notch inhibition models","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays plus in vivo model organism confirmation, but the MAML2 variant is single-patient; multiple orthogonal methods","pmids":["36898841"],"is_preprint":false}],"current_model":"MAML2 is a transcriptional coactivator whose C-terminal transactivation domain (TAD1) directly recruits CBP/p300 via the KIX domain; in the oncogenic CRTC1-MAML2 fusion, the CRTC1 N-terminus constitutively tethers CREB and CBP/p300 to CREB target gene promoters, driving aberrant expression of AREG (which activates autocrine EGFR signaling), PGC-1α4/PPARγ/IGF-1 circuitry, and MYC target genes, making sustained fusion expression essential for MEC tumor growth; in parallel, YAP1-MAML2 fusions act through TEAD-dependent YAP transcriptional activity—resistant to Hippo suppression and capable of phase-separation-mediated selective gene amplification—to drive tumorigenesis in poromas, meningiomas, and related neoplasms."},"narrative":{"mechanistic_narrative":"MAML2 is a transcriptional coactivator that bridges DNA-bound transcription factors to the CBP/p300 acetyltransferase machinery: its C-terminal transactivation domain 1 (TAD1) binds directly to the CBP KIX domain through an ~20-residue segment that contacts the same KIX surface used by MLL1, providing the molecular basis for coactivator recruitment [PMID:26274502]. In its native context the N-terminal basic domain of MAML2 binds the Notch intracellular domain to support Notch target gene transcription, and loss or dominant-negative disruption of this function impairs Notch signaling—silencing MAML2 downregulates Notch targets [PMID:27207652], and a pathogenic MAML2 variant acts dominant-negatively to block HES1-dependent thyroid hormone biosynthesis genes, linking MAML2 to congenital hypothyroidism through Notch control of thyroid cells [PMID:36898841]. MAML2's dominant disease relevance is as the 3' partner in recurrent oncogenic fusions. In the CRTC1(MECT1)-MAML2 fusion of mucoepidermoid carcinoma, the MAML2 N-terminal Notch-binding domain is replaced by the CRTC1 N-terminus, which tethers CREB and recruits p300/CBP to constitutively activate CREB-dependent transcription [PMID:15961999, PMID:14720503]; this transforming activity depends on an intact CREB-binding domain [PMID:16103063] and on sustained fusion expression, which is required for tumor growth and is a causal, 100%-penetrant driver of salivary gland tumors in mice [PMID:16652146, PMID:33830080]. The fusion drives a network of mitogenic programs—autocrine AREG/EGFR signaling [PMID:23975434], a PGC-1α4/PPARγ/IGF-1 circuit [PMID:33626346], MYC target gene activation through direct MYC interaction [PMID:25071166], and CREB-dependent induction of the lncRNA LINC00473, which binds NONO to reinforce CREB-mediated transcription [PMID:29353885]. In a parallel oncogenic context, YAP1-MAML2 fusions act through Hippo-resistant, TEAD-dependent YAP transcriptional activity to drive poromas and meningioma-like tumors [PMID:31145701, PMID:36008139], and form phase-separated condensates that selectively amplify a subset of YAP target genes including CTGF and CYR61 [PMID:38315854].","teleology":[{"year":2004,"claim":"Established that the CRTC1(WAMTP1)-MAML2 fusion swaps out the MAML2 N-terminal basic domain needed for Notch ICD binding, repositioning the fusion away from native Notch coactivation.","evidence":"Fusion cloning, domain deletion/mutation analysis, immunofluorescence co-localization, and Notch target gene expression in primary MEC tumors","pmids":["14720503"],"confidence":"Medium","gaps":["Did not establish the gain-of-function transcriptional mechanism of the fusion","Altered Notch targets observed only correlatively in tumor samples"]},{"year":2005,"claim":"Defined the gain-of-function mechanism: the fusion tethers CREB and recruits p300/CBP to constitutively activate CREB target genes, and showed CREB DNA binding is required for transformation.","evidence":"Co-IP, reporter assays, dominant-negative CREB blocking, and epithelial transformation assays; reinforced by in-frame deletion of the CREB-binding domain abolishing transforming activity in RK3E cells","pmids":["15961999","16103063"],"confidence":"High","gaps":["Did not map the precise MAML2 surface recruiting p300/CBP","Notch target genes unchanged, leaving native MAML2 contribution unaddressed"]},{"year":2006,"claim":"Showed that sustained fusion expression is continuously required for tumor cell growth, establishing oncogene dependence.","evidence":"Hairpin RNAi knockdown, colony formation, RNAi-resistant rescue, and xenograft assays in t(11;19) MEC lines","pmids":["16652146"],"confidence":"High","gaps":["Did not identify the downstream effectors mediating dependence"]},{"year":2007,"claim":"Showed that a distinct MLL-MAML2 fusion also deletes the Notch-binding domain and acts dominant-negatively on Notch target transcription.","evidence":"Breakpoint RT-PCR/sequencing and luciferase reporter for NOTCH1-ICD-driven HES1 activity","pmids":["17551948"],"confidence":"Medium","gaps":["Limited to a reporter readout without cellular transformation data","Biological consequence in primary tumors not established"]},{"year":2013,"claim":"Identified autocrine AREG/EGFR signaling as a druggable downstream output of the CRTC1-MAML2/CREB axis.","evidence":"Expression analysis, fusion knockdown, pharmacological EGFR inhibition, and MEC xenografts","pmids":["23975434"],"confidence":"High","gaps":["Did not establish whether EGFR signaling alone accounts for growth dependence"]},{"year":2014,"claim":"Revealed a gain-of-function interaction with MYC, expanding the fusion's transcriptional program to MYC targets required for transformation.","evidence":"Co-IP of the fusion with MYC, expression profiling, and transformation assays in endogenous-fusion MEC cells","pmids":["25071166"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal structural mapping of the interaction","Direct vs indirect nature of the MYC interaction not resolved"]},{"year":2015,"claim":"Provided the molecular basis for coactivator recruitment by mapping direct MAML2 TAD1 binding to the CBP KIX domain at the MLL1-binding surface.","evidence":"In vitro peptide binding (NMR/biochemical) and sequence/structural analysis of the KIX interface","pmids":["26274502"],"confidence":"Medium","gaps":["No mutagenesis validation of the interface in a cellular context","Affinity measured for an isolated peptide, not full-length fusion"]},{"year":2018,"claim":"Showed CREB-dependent induction of the lncRNA LINC00473, which binds NONO to amplify fusion-driven CREB transcription and supports tumor growth.","evidence":"Expression profiling, siRNA knockdown, xenografts, RNA-ISH, and RNA pull-down for NONO","pmids":["29353885"],"confidence":"Medium","gaps":["Single lab; mechanism of NONO-mediated transcriptional enhancement incompletely defined"]},{"year":2021,"claim":"Established CRTC1-MAML2 as a causal, fully penetrant in vivo driver and uncovered cooperating p16-CDK4/6-RB pathway alterations and PGC-1α4/PPARγ/IGF-1 circuitry as combination-therapy targets.","evidence":"Conditional transgenic mouse model, dox-inducible shRNA in xenografts, pathway analysis, and combined EGFR/CDK4/6 or IGF-1R/PPARγ pharmacology","pmids":["33830080","33626346"],"confidence":"High","gaps":["Relative contribution of the parallel mitogenic circuits to tumor maintenance not ranked","PGC-1α4/PPARγ/IGF-1 findings from a single lab"]},{"year":2022,"claim":"Demonstrated that YAP1-MAML2 fusions drive tumors via Hippo-resistant, TEAD-dependent YAP activity, with the YAP component being the critical oncogenic driver.","evidence":"In vivo mouse expression model, expression profiling vs NF2-mutant meningiomas, constitutively active YAP1 mutagenesis, and YAP-TEAD inhibitor treatment ex vivo; building on RNA-seq/reporter identification of the fusion in poromas","pmids":["36008139","31145701"],"confidence":"High","gaps":["Functional contribution of the MAML2 portion to the YAP fusion not isolated","Mechanism of Hippo resistance not structurally defined"]},{"year":2023,"claim":"Linked native MAML2 loss-of-function to human disease, showing a dominant-negative variant blocks HES1-dependent thyroid hormone biosynthesis and causes congenital hypothyroidism.","evidence":"Variant identification, reporter/functional assays in HEK293T and thyroid cells, thyroid organoids, and zebrafish/mouse Notch inhibition models","pmids":["36898841"],"confidence":"Medium","gaps":["Based on a single patient variant","Generalizability to other MAML2 loss-of-function alleles untested"]},{"year":2024,"claim":"Resolved how YAP1-MAML2 organizes transcription, showing phase-separated condensates selectively amplify a small subset of target genes rather than the bulk program.","evidence":"Live-cell phase-separation imaging, chemogenetic condensate dissolution at matched protein levels, and paired transcriptome comparison","pmids":["38315854"],"confidence":"Medium","gaps":["Single lab with a novel chemogenetic tool","Mechanism selecting which genes require condensates is undefined"]},{"year":null,"claim":"How native full-length MAML2 coactivation is regulated and integrated across distinct transcription factor partners (Notch, CREB, TEAD) in non-fusion physiological contexts remains incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length MAML2 in any native complex","Endogenous MAML2 function in normal tissues largely uncharacterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6,11,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,7,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,11,12]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[14]}],"complexes":["CREB transcriptional complex","TEAD transcriptional complex"],"partners":["CREB1","CREBBP","EP300","MYC","NOTCH1","TEAD","NONO"],"other_free_text":[]}},"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":212,"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":201,"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":171,"is_preprint":false},{"pmid":"19749740","id":"PMC_19749740","title":"Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma.","date":"2009","source":"Modern pathology : an official journal of the United States and Canadian Academy of 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A, Pathological anatomy and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/2508309","citation_count":9,"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":"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":7,"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":7,"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":"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":"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":"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":"37589282","id":"PMC_37589282","title":"Salivary Gland Neoplasms With a Unique Trabecular Histology and MAML2 Translocation : A Trabecular Variant of a Mucoepidermoid Carcinoma.","date":"2023","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37589282","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":"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":"37489594","id":"PMC_37489594","title":"Significance of YAP1-MAML2 rearrangement and GTF2I mutation in the diagnosis and differential diagnosis of metaplastic thymoma.","date":"2023","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37489594","citation_count":4,"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":"36723803","id":"PMC_36723803","title":"YAP1::MAML2 fusions in poromatosis: A report of two patients.","date":"2023","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36723803","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53605,"output_tokens":4663,"usd":0.11538,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12714,"output_tokens":4158,"usd":0.08376,"stage2_stop_reason":"end_turn"},"total_usd":0.19914,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"The MECT1-MAML2 (CRTC1-MAML2) fusion protein binds to CREB and recruits p300/CBP into the CREB transcriptional complex through a binding domain on the MAML2 portion, constitutively activating CREB-dependent transcription and inducing expression of multiple CREB target genes. The transforming activity of MECT1-MAML2 was markedly reduced by blocking CREB DNA binding.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, gene expression analysis, dominant-negative CREB blocking, transformation assays in epithelial cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, functional mutagenesis (CREB-blocking), transformation assay, and gene expression profiling in a single rigorous study; replicated by independent lab (PMID:16103063)\",\n      \"pmids\": [\"15961999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The transforming activity of the MECT1-MAML2 fusion oncogene depends on an intact CREB-binding domain derived from the MECT1/TORC1 N-terminus; small in-frame deletions within this CREB-binding domain completely abolished transforming activity in RK3E epithelial cells. The fusion strongly activated cAMP/CREB-regulated genes but did not alter known Notch-regulated target genes in expression profiling experiments.\",\n      \"method\": \"In-frame deletion mutagenesis of the CREB-binding domain, transformation assay in RK3E cells, doxycycline-regulated expression system, global gene expression profiling, RT-PCR validation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with functional rescue, complemented by genome-wide expression profiling, validated in multiple cell lines including endogenous-fusion-expressing MEC cells; consistent with PMID:15961999\",\n      \"pmids\": [\"16103063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sustained expression of the MECT1-MAML2 fusion is required for tumor cell growth: RNAi-mediated knockdown of the fusion peptide caused ≥90% colony growth inhibition in MEC tumor cell lines carrying the t(11;19) rearrangement. Re-expression of an RNAi-resistant mutant MECT1-MAML2 partially rescued growth inhibition, confirming on-target specificity.\",\n      \"method\": \"Hairpin RNAi knockdown, colony formation assay, rescue experiment with RNAi-resistant mutant, in vivo xenograft in nude mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined cellular phenotype, genetic rescue control, confirmed in vivo; multiple orthogonal methods in one study\",\n      \"pmids\": [\"16652146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The WAMTP1(CRTC1)-MAML2 fusion protein loses the N-terminal basic domain of MAML2 required for binding to intracellular Notch (Notch ICD). Mutation analysis identified two regions in the WAMTP1 N-terminus important for nuclear localization (amino acids 11-20) and for co-localization with MAML2 and Notch1 ICD in nuclear granules (amino acids 21-42). Analysis of Notch target genes in fusion-positive vs. negative MEC tumors showed upregulation of HES5 and downregulation of MASH1, indicating altered Notch signaling.\",\n      \"method\": \"Fusion gene cloning, domain deletion/mutation analysis, immunofluorescence co-localization, Notch target gene expression analysis in primary tumor samples\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mutation analysis with co-localization readout and gene expression in primary tumors, single lab\",\n      \"pmids\": [\"14720503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The CRTC1-MAML2 fusion oncoprotein co-activates CREB transcription factor to induce upregulation of the EGFR ligand Amphiregulin (AREG), which then activates EGFR signaling in an autocrine manner promoting MEC cell growth and survival. CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition in vitro and in vivo.\",\n      \"method\": \"Gene expression analysis, RNA interference knockdown of CRTC1-MAML2, pharmacological EGFR inhibition, human MEC xenograft models in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockdown with defined downstream pathway, pharmacological validation, in vivo xenograft confirmation; replicated in subsequent studies (PMID:33830080, PMID:35251626)\",\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 involved in cell growth, metabolism, survival, and tumorigenesis. This gain-of-function interaction with MYC is necessary for C1/M2-driven cell transformation.\",\n      \"method\": \"Co-immunoprecipitation of C1/M2 with MYC, gene expression profiling, transformation assay, validation in human MEC tumor cells harboring the t(11;19) translocation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of fusion with MYC plus transformation assay, validated in endogenous-fusion MEC cells, single lab\",\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 TAD1, conserved in MAML2 orthologs and paralogs, contacts a KIX surface previously shown to bind MLL1, sharing sequence and structural similarity with MLL1 at those contact positions. This provides the molecular basis for constitutive CBP/p300 recruitment by CRTC1/3-MAML2 fusion proteins.\",\n      \"method\": \"In vitro peptide binding assay (NMR/biochemical), sequence and structural analysis of KIX-binding interface\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assay with structural analysis, single lab, no mutagenesis validation of the interface in a cellular context\",\n      \"pmids\": [\"26274502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTC1-MAML2 is a causal oncogenic driver for MEC: doxycycline-induced knockdown blocked growth of established MEC xenografts; conditional transgenic Cre-induced CRTC1-MAML2 expression caused 100% penetrant salivary gland tumor formation in mice resembling human MEC histologically and molecularly. Molecular analysis revealed altered p16-CDK4/6-RB pathway activity as a cooperating event; co-targeting AREG/EGFR signaling (Erlotinib) and CDK4/6 (Palbociclib) produced enhanced anti-tumor responses in vitro and in vivo.\",\n      \"method\": \"Doxycycline-inducible shRNA knockdown in xenografts, conditional transgenic mouse model (Cre-induced expression), molecular pathway analysis, pharmacological combination therapy in vitro and in vivo\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional transgenic model with 100% penetrance, loss-of-function in xenografts, multiple orthogonal methods; definitive causal driver evidence\",\n      \"pmids\": [\"33830080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1α splice variant PGC-1α4, which regulates PPARγ-mediated IGF-1 expression, creating an autocrine mitogenic circuit. C1/M2-positive tumor cells are selectively sensitive to IGF-1R inhibition and to PPARγ inverse agonists.\",\n      \"method\": \"Gene expression profiling, small-molecule drug screens, knockdown/overexpression of pathway components, pharmacological inhibition of IGF-1R and PPARγ in MEC cell lines and primary tumors\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression profiling plus pharmacological validation, single lab, consistent across cell lines and primary tumors\",\n      \"pmids\": [\"33626346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRTC1-MAML2 fusion-induced transcription of LINC00473 (a lncRNA) is dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. LINC00473 depletion reduced MEC cell proliferation and survival in vitro and blocked tumor growth in xenografts. LINC00473 binds the cAMP signaling component NONO, enhancing CRTC1-MAML2-driven CREB-mediated transcription.\",\n      \"method\": \"Gene expression profiling, siRNA knockdown, in vivo xenograft, RNA in situ hybridization, RNA pull-down assay for NONO binding\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with in vivo confirmation plus RNA pulldown for binding partner, single lab\",\n      \"pmids\": [\"29353885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The MLL-MAML2 fusion, created by inv(11)(q21q23), encodes a chimeric protein in which the N-terminal basic domain of MAML2 (required for binding Notch ICD) is deleted. Luciferase assay demonstrated that MLL-MAML2 suppresses HES1 promoter activation by the NOTCH1 intracellular domain, indicating disruption of Notch signaling.\",\n      \"method\": \"RT-PCR and sequencing of fusion breakpoints, luciferase reporter assay for NOTCH1-ICD-driven HES1 promoter activity\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter assay showing dominant-negative effect on Notch target, single lab, limited functional follow-up\",\n      \"pmids\": [\"17551948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1-MAML2 fusion proteins (identified by RNA-seq in poromas and porocarcinomas) strongly transactivate a TEAD reporter and promote anchorage-independent growth, confirming tumorigenic activity driven by YAP1/TEAD-dependent transcription. The YAP1 N-terminus (retained in the fusion) directs nuclear localization detectable by immunohistochemistry, while the YAP1 C-terminus is lost.\",\n      \"method\": \"RNA sequencing, RT-PCR, FISH confirmation of genomic rearrangements, TEAD luciferase reporter assay, anchorage-independent growth assay, immunohistochemistry\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reporter assay, functional transformation assay, genomic confirmation by multiple methods, replicated across 104 tumor samples; replicated in subsequent studies (PMID:36008139, PMID:38315854)\",\n      \"pmids\": [\"31145701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YAP1-MAML2 fusion primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Expression of YAP1-MAML2 in mice induces meningioma-like tumors; constitutively active YAP1 (S127/397A) induces similar tumors, indicating that the YAP component is the critical oncogenic driver. Treatment with YAP-TEAD inhibitors inhibited viability of YAP1-MAML2-driven mouse tumors ex vivo.\",\n      \"method\": \"In vivo mouse expression model, gene expression profiling comparing YAP1 fusion-positive vs NF2 mutant meningiomas, YAP-TEAD inhibitor treatment ex vivo, constitutively active YAP1 mutagenesis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse tumor model, mutagenesis to separate YAP vs MAML2 contributions, pharmacological validation, multiple orthogonal methods\",\n      \"pmids\": [\"36008139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YAP1-MAML2 fusion undergoes phase separation (PS) and forms liquid-like condensates with hallmarks of transcriptional activity. Using a chemogenetic tool to dissolve condensates at identical protein levels, PS was found to selectively further amplify expression of a small fraction of YAP1-MAML2 target genes (including CTGF and CYR61), while the majority of YAP1-MAML2-regulated genes are not affected by PS and can be activated by diffuse TF complexes.\",\n      \"method\": \"Live-cell phase separation imaging, chemogenetic condensate dissolution tool, comparative transcriptome analysis under phase-separated vs. non-phase-separated conditions\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemogenetic tool with paired transcriptomic readout provides mechanistic resolution, single lab, novel method\",\n      \"pmids\": [\"38315854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Stilbenoids (resveratrol and pterostilbene) induce de novo methylation at the MAML2 enhancer region, leading to transcriptional silencing of MAML2. This coincides with increased occupancy of repressive histone marks, decreased activating marks, binding of DNMT3B, and decreased occupancy of OCT1 transcription factor at the MAML2 enhancer, resulting in downregulation of NOTCH target genes in breast cancer cells.\",\n      \"method\": \"Genome-wide Illumina 450K DNA methylation array, ChIP for histone marks and DNMT3B/OCT1, gene expression analysis\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal epigenomic methods identifying DNMT3B as writer and OCT1 as displaced reader at MAML2 enhancer, single lab\",\n      \"pmids\": [\"27207652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A pathogenic MAML2 variant identified in a patient with congenital hypothyroidism exerts a dominant-negative effect on canonical Notch signaling and on thyroid hormone biosynthesis gene expression. In vitro functional assays in HEK293T and thyroid cells, organoid culture, and zebrafish/mouse models showed that Notch signaling within thyroid cells directly affects thyroid hormone biosynthesis; the MAML2 variant blocked HES1-dependent hormone biosynthesis gene expression.\",\n      \"method\": \"NGS variant identification, in vitro reporter/functional assays in HEK293T and Nthy-ori 3.1 cells, primary mouse thyroid organoid culture with transcriptome sequencing, zebrafish and mouse Notch inhibition models\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays plus in vivo model organism confirmation, but the MAML2 variant is single-patient; multiple orthogonal methods\",\n      \"pmids\": [\"36898841\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAML2 is a transcriptional coactivator whose C-terminal transactivation domain (TAD1) directly recruits CBP/p300 via the KIX domain; in the oncogenic CRTC1-MAML2 fusion, the CRTC1 N-terminus constitutively tethers CREB and CBP/p300 to CREB target gene promoters, driving aberrant expression of AREG (which activates autocrine EGFR signaling), PGC-1α4/PPARγ/IGF-1 circuitry, and MYC target genes, making sustained fusion expression essential for MEC tumor growth; in parallel, YAP1-MAML2 fusions act through TEAD-dependent YAP transcriptional activity—resistant to Hippo suppression and capable of phase-separation-mediated selective gene amplification—to drive tumorigenesis in poromas, meningiomas, and related neoplasms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAML2 is a transcriptional coactivator that bridges DNA-bound transcription factors to the CBP/p300 acetyltransferase machinery: its C-terminal transactivation domain 1 (TAD1) binds directly to the CBP KIX domain through an ~20-residue segment that contacts the same KIX surface used by MLL1, providing the molecular basis for coactivator recruitment [#6]. In its native context the N-terminal basic domain of MAML2 binds the Notch intracellular domain to support Notch target gene transcription, and loss or dominant-negative disruption of this function impairs Notch signaling—silencing MAML2 downregulates Notch targets [#14], and a pathogenic MAML2 variant acts dominant-negatively to block HES1-dependent thyroid hormone biosynthesis genes, linking MAML2 to congenital hypothyroidism through Notch control of thyroid cells [#15]. MAML2's dominant disease relevance is as the 3' partner in recurrent oncogenic fusions. In the CRTC1(MECT1)-MAML2 fusion of mucoepidermoid carcinoma, the MAML2 N-terminal Notch-binding domain is replaced by the CRTC1 N-terminus, which tethers CREB and recruits p300/CBP to constitutively activate CREB-dependent transcription [#0, #3]; this transforming activity depends on an intact CREB-binding domain [#1] and on sustained fusion expression, which is required for tumor growth and is a causal, 100%-penetrant driver of salivary gland tumors in mice [#2, #7]. The fusion drives a network of mitogenic programs—autocrine AREG/EGFR signaling [#4], a PGC-1\\u03b14/PPAR\\u03b3/IGF-1 circuit [#8], MYC target gene activation through direct MYC interaction [#5], and CREB-dependent induction of the lncRNA LINC00473, which binds NONO to reinforce CREB-mediated transcription [#9]. In a parallel oncogenic context, YAP1-MAML2 fusions act through Hippo-resistant, TEAD-dependent YAP transcriptional activity to drive poromas and meningioma-like tumors [#11, #12], and form phase-separated condensates that selectively amplify a subset of YAP target genes including CTGF and CYR61 [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that the CRTC1(WAMTP1)-MAML2 fusion swaps out the MAML2 N-terminal basic domain needed for Notch ICD binding, repositioning the fusion away from native Notch coactivation.\",\n      \"evidence\": \"Fusion cloning, domain deletion/mutation analysis, immunofluorescence co-localization, and Notch target gene expression in primary MEC tumors\",\n      \"pmids\": [\"14720503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish the gain-of-function transcriptional mechanism of the fusion\", \"Altered Notch targets observed only correlatively in tumor samples\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the gain-of-function mechanism: the fusion tethers CREB and recruits p300/CBP to constitutively activate CREB target genes, and showed CREB DNA binding is required for transformation.\",\n      \"evidence\": \"Co-IP, reporter assays, dominant-negative CREB blocking, and epithelial transformation assays; reinforced by in-frame deletion of the CREB-binding domain abolishing transforming activity in RK3E cells\",\n      \"pmids\": [\"15961999\", \"16103063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the precise MAML2 surface recruiting p300/CBP\", \"Notch target genes unchanged, leaving native MAML2 contribution unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that sustained fusion expression is continuously required for tumor cell growth, establishing oncogene dependence.\",\n      \"evidence\": \"Hairpin RNAi knockdown, colony formation, RNAi-resistant rescue, and xenograft assays in t(11;19) MEC lines\",\n      \"pmids\": [\"16652146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the downstream effectors mediating dependence\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that a distinct MLL-MAML2 fusion also deletes the Notch-binding domain and acts dominant-negatively on Notch target transcription.\",\n      \"evidence\": \"Breakpoint RT-PCR/sequencing and luciferase reporter for NOTCH1-ICD-driven HES1 activity\",\n      \"pmids\": [\"17551948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited to a reporter readout without cellular transformation data\", \"Biological consequence in primary tumors not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified autocrine AREG/EGFR signaling as a druggable downstream output of the CRTC1-MAML2/CREB axis.\",\n      \"evidence\": \"Expression analysis, fusion knockdown, pharmacological EGFR inhibition, and MEC xenografts\",\n      \"pmids\": [\"23975434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether EGFR signaling alone accounts for growth dependence\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a gain-of-function interaction with MYC, expanding the fusion's transcriptional program to MYC targets required for transformation.\",\n      \"evidence\": \"Co-IP of the fusion with MYC, expression profiling, and transformation assays in endogenous-fusion MEC cells\",\n      \"pmids\": [\"25071166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal structural mapping of the interaction\", \"Direct vs indirect nature of the MYC interaction not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the molecular basis for coactivator recruitment by mapping direct MAML2 TAD1 binding to the CBP KIX domain at the MLL1-binding surface.\",\n      \"evidence\": \"In vitro peptide binding (NMR/biochemical) and sequence/structural analysis of the KIX interface\",\n      \"pmids\": [\"26274502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of the interface in a cellular context\", \"Affinity measured for an isolated peptide, not full-length fusion\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CREB-dependent induction of the lncRNA LINC00473, which binds NONO to amplify fusion-driven CREB transcription and supports tumor growth.\",\n      \"evidence\": \"Expression profiling, siRNA knockdown, xenografts, RNA-ISH, and RNA pull-down for NONO\",\n      \"pmids\": [\"29353885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanism of NONO-mediated transcriptional enhancement incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CRTC1-MAML2 as a causal, fully penetrant in vivo driver and uncovered cooperating p16-CDK4/6-RB pathway alterations and PGC-1\\u03b14/PPAR\\u03b3/IGF-1 circuitry as combination-therapy targets.\",\n      \"evidence\": \"Conditional transgenic mouse model, dox-inducible shRNA in xenografts, pathway analysis, and combined EGFR/CDK4/6 or IGF-1R/PPAR\\u03b3 pharmacology\",\n      \"pmids\": [\"33830080\", \"33626346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of the parallel mitogenic circuits to tumor maintenance not ranked\", \"PGC-1\\u03b14/PPAR\\u03b3/IGF-1 findings from a single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that YAP1-MAML2 fusions drive tumors via Hippo-resistant, TEAD-dependent YAP activity, with the YAP component being the critical oncogenic driver.\",\n      \"evidence\": \"In vivo mouse expression model, expression profiling vs NF2-mutant meningiomas, constitutively active YAP1 mutagenesis, and YAP-TEAD inhibitor treatment ex vivo; building on RNA-seq/reporter identification of the fusion in poromas\",\n      \"pmids\": [\"36008139\", \"31145701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of the MAML2 portion to the YAP fusion not isolated\", \"Mechanism of Hippo resistance not structurally defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked native MAML2 loss-of-function to human disease, showing a dominant-negative variant blocks HES1-dependent thyroid hormone biosynthesis and causes congenital hypothyroidism.\",\n      \"evidence\": \"Variant identification, reporter/functional assays in HEK293T and thyroid cells, thyroid organoids, and zebrafish/mouse Notch inhibition models\",\n      \"pmids\": [\"36898841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on a single patient variant\", \"Generalizability to other MAML2 loss-of-function alleles untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved how YAP1-MAML2 organizes transcription, showing phase-separated condensates selectively amplify a small subset of target genes rather than the bulk program.\",\n      \"evidence\": \"Live-cell phase-separation imaging, chemogenetic condensate dissolution at matched protein levels, and paired transcriptome comparison\",\n      \"pmids\": [\"38315854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with a novel chemogenetic tool\", \"Mechanism selecting which genes require condensates is undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How native full-length MAML2 coactivation is regulated and integrated across distinct transcription factor partners (Notch, CREB, TEAD) in non-fusion physiological contexts remains incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length MAML2 in any native complex\", \"Endogenous MAML2 function in normal tissues largely uncharacterized in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 11, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 7, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 11, 12]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"CREB transcriptional complex\", \"TEAD transcriptional complex\"],\n    \"partners\": [\"CREB1\", \"CREBBP\", \"EP300\", \"MYC\", \"NOTCH1\", \"TEAD\", \"NONO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}