{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMLLT1, also known as ENL, is a YEATS‐domain–containing protein that functions as an epigenetic “reader” by binding acetylated (and crotonylated) lysine residues on histone tails. Structural and biochemical studies have demonstrated that its highly conserved YEATS domain is essential for recognizing promoter‐associated histone acetylation marks, thereby facilitating the recruitment of RNA polymerase II and the assembly of chromatin‐remodeling complexes such as SWI/SNF and the super elongation complex. These interactions support transcriptional elongation and the maintenance of active gene expression programs during normal development and hematopoiesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nIn oncogenic settings, MLLT1 is often hijacked by chromosomal translocations—most notably in the formation of MLL‐ENL fusion proteins—that drive aggressive forms of leukemia. In response to DNA damage, ATM phosphorylates MLLT1 at conserved SQ motifs, enhancing its interaction with Polycomb repressive complex components and thereby switching its role from promoting transcriptional elongation to mediating transcriptional silencing via H2A ubiquitination. Moreover, cancer‐associated mutations altering the conformation of the YEATS domain modify its affinity for acetylated histones and can promote aberrant self-association. These alterations contribute to dysregulated expression of oncogenic gene programs, and recent peptide‐inhibition studies that target these interactions underscore the therapeutic potential of disrupting MLLT1 function in leukemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its well‐characterized role in transcriptional regulation and leukemogenesis, MLLT1 displays dynamic, tissue‐specific expression and alternative splicing that suggest additional functions during development and in disease contexts. Its genomic locus is prone to spatial juxtaposition with various partner genes, facilitating complex translocation events, and MLLT1‐driven gene expression has been implicated in the transformation of specific hematopoietic progenitor subpopulations. Furthermore, emerging evidence indicates that noncoding RNAs—such as circVRK1, which can sponge miR-150-5p to control MLLT1 expression—modulate its activity in stress responses, including in ischemic injury of brain microvascular endothelial cells. These multifaceted roles underscore the importance of MLLT1 in normal cellular differentiation as well as in pathological conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "18"}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zuqin Nie, Zhijiang Yan, Everett H Chen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Discov (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2159-8290.CD-20-1459"}], "href": "https://doi.org/10.1158/2159-8290.CD-20-1459"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34853079"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34853079"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sang-Guk Lee, Tae Sung Park, Sung Chul Won, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Three-way translocation involving MLL, MLLT1, and a novel third partner, NRXN1, in a patient with acute lymphoblastic leukemia and t(2;19;11) (p12;p13.3;q23)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Genet Cytogenet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cancergencyto.2009.10.009"}], "href": "https://doi.org/10.1016/j.cancergencyto.2009.10.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20113834"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20113834"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Loredana Elia, Sara Grammatico, Francesca Paoloni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical outcome and monitoring of minimal residual disease in patients with acute lymphoblastic leukemia expressing the MLL/ENL fusion gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hematol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajh.22161"}], "href": "https://doi.org/10.1002/ajh.22161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21953510"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21953510"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Emanuel Maethner, Maria-Paz Garcia-Cuellar, Constanze Breitinger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2013.03.038"}], "href": "https://doi.org/10.1016/j.celrep.2013.03.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23623499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23623499"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Nisha N Barretto, Dean S Karahalios, Dewen You, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An AF9/ENL-targted peptide with therapeutic potential in mixed lineage leukemias."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Ther Oncol (2014)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25509985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25509985"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ayako Ui, Yuko Nagaura, Akira Yasui "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional elongation factor ENL phosphorylated by ATM recruits polycomb and switches off transcription for DSB repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2015.03.023"}], "href": "https://doi.org/10.1016/j.molcel.2015.03.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25921070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25921070"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Elizabeth J Perlman, Samantha Gadd, Stefan T Arold, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms10013"}], "href": "https://doi.org/10.1038/ncomms10013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26635203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26635203"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Xiaomin Ni, Allyn T Londregan, Dafydd R Owen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "ACS Chem Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acschembio.0c00960"}], "href": "https://doi.org/10.1021/acschembio.0c00960"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33749253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33749253"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Hsiangyu Hu, Nirmalya Saha, Yuting Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41375-022-01765-0"}], "href": "https://doi.org/10.1038/s41375-022-01765-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36435883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36435883"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Michaël Gué, Jian-Sheng Sun, Thomas Boudier "}, {"type": "b", "children": [{"type": "t", "text": "Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2407-6-20"}], "href": "https://doi.org/10.1186/1471-2407-6-20"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16433901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16433901"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Amol Ugale, Gudmundur L Norddahl, Martin Wahlestedt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2014.10.036"}], "href": "https://doi.org/10.1016/j.celrep.2014.10.036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25456127"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25456127"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Mary C Wallingford, Rachel Filkins, Danielle Adams, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel isoform of the leukemia-associated MLLT1 (ENL/LTG19) protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene Expr Patterns (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gep.2014.11.003"}], "href": "https://doi.org/10.1016/j.gep.2014.11.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25481096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25481096"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Theresa Okeyo-Owuor, Yanan Li, Riddhi M Patel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood Adv (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/bloodadvances.2019000554"}], "href": "https://doi.org/10.1182/bloodadvances.2019000554"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31405949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31405949"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Lina Tan, Lingjun Wang, Jiajun Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circvrk1 downregulation attenuates brain microvascular endothelial cell damage induced by oxygen-glucose deprivation through modulating the miR-150-5p/MLLT1 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Brain Res (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00221-023-06555-3"}], "href": "https://doi.org/10.1007/s00221-023-06555-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36735043"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36735043"}]}]}]}