{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The Mastermind‐like 2 (MAML2) protein is a transcriptional coactivator that normally functions as a critical component of the canonical Notch signaling pathway by binding to the intracellular domain of Notch and the CSL (CBF‐1/RBP‐J) DNA–binding complex to facilitate transcriptional activation (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In several human neoplasms—most notably in mucoepidermoid carcinoma (MEC) of the salivary glands—MAML2 is found fused in-frame with diverse partners such as MECT1 (also called CRTC1), CRTC3, or even YAP1, thereby generating chimeric oncoproteins that alter normal transcriptional regulation. For example, the CRTC1–MAML2 fusion has been shown to function as a potent, ligand-independent coactivator that aberrantly activates Notch target genes (including HES1) and CREB–responsive genes, thereby contributing to epithelial cell transformation and tumor maintenance (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " Similarly, alternative MAML2 fusions (such as YAP1–MAML2) have been identified in benign sweat gland tumors (poromas) and metaplastic thymomas, indicating that disruption of normal MAML2 function plays a significant role in tumorigenesis by deregulating both Notch and other signaling pathways (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " In addition, MAML2 sequences have been found fused to MLL in secondary acute leukemias, suggesting that the oncogenic potential of MAML2‐containing fusion proteins extends beyond epithelial tumors and may function in a context‐dependent manner to perturb differentiation and cellular proliferation (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In its normal state, MAML2 provides a controlled platform for Notch‐mediated transcription; however, when fused to partners that confer constitutive or ectopic activation, the chimeric proteins retain the C‐terminal transcriptional activation domain of MAML2. This aberrant activation results in altered expression of downstream target genes—including key regulators of cell fate, proliferation, and survival such as those in the epidermal growth factor receptor (EGFR) pathway—as well as disruption of the fine-tuned balance between differentiation and maintenance of stemness (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " The clinical impact of these rearrangements is exemplified in MEC, where the presence of MAML2 fusions is often associated with distinct histologic subtypes and a more indolent clinical course, although additional genetic alterations (for example, deletions in CDKN2A) may modulate the disease outcome."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, MAML2 plays a dual role: under physiological conditions, it serves as an essential coactivator in Notch signaling, while in the context of gene fusions it becomes part of oncogenic chimeric proteins that drive tumorigenesis across a spectrum of neoplasms by dysregulating transcriptional programs. These insights not only improve diagnostic accuracy in challenging tumors but also suggest that targeting the aberrant signaling cascades activated by MAML2 fusions could have therapeutic potential.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Giovanni Tonon, Sanjay Modi, Lizi Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1083"}], "href": "https://doi.org/10.1038/ng1083"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12539049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12539049"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sey-En Lin, Toshinao Oyama, Takahiro Nagase, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M209529200"}], "href": "https://doi.org/10.1074/jbc.M209529200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12386158"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12386158"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Raja R Seethala, Sanja Dacic, Kathleen Cieply, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Surg Pathol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/PAS.0b013e3181de3021"}], "href": "https://doi.org/10.1097/PAS.0b013e3181de3021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20588178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20588178"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mitsukuni Okabe, Satoru Miyabe, Hitoshi Nagatsuka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-05-2376"}], "href": "https://doi.org/10.1158/1078-0432.CCR-05-2376"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16818685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16818685"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "André Fehr, Kerstin Röser, Klaus Heidorn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new type of MAML2 fusion in mucoepidermoid carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20522"}], "href": "https://doi.org/10.1002/gcc.20522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18050304"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18050304"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Fredrik Enlund, Afrouz Behboudi, Ywonne Andrén, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2003.09.007"}], "href": "https://doi.org/10.1016/j.yexcr.2003.09.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14720503"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14720503"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Marina Vivero, Phani Davineni, Valentina Nardi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Metaplastic thymoma: a distinctive thymic neoplasm characterized by YAP1-MAML2 gene fusions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mod Pathol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41379-019-0382-x"}], "href": "https://doi.org/10.1038/s41379-019-0382-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31641231"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31641231"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Cristina R Antonescu, Brendan C Dickson, Yun-Shao Sung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recurrent YAP1 and MAML2 Gene Rearrangements in Retiform and Composite Hemangioendothelioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Surg Pathol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/PAS.0000000000001575"}], "href": "https://doi.org/10.1097/PAS.0000000000001575"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32991341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32991341"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Noriko Nemoto, Kazumi Suzukawa, Seiichi Shimizu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20467"}], "href": "https://doi.org/10.1002/gcc.20467"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17551948"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17551948"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Simone Brabletz, Karolina Bajdak, Simone Meidhof, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2010.349"}], "href": "https://doi.org/10.1038/emboj.2010.349"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21224848"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21224848"}]}]}]}