title: DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis.
abstract: Chromosomal translocations of the mixed lineage leukemia (MLL) gene are a common cause of acute leukemias. The oncogenic function of MLL fusion proteins is, in part, mediated through aberrant activation of Hoxa genes and Meis1, among others. Here we demonstrate using a tamoxifen-inducible Cre-mediated loss of function mouse model that DOT1L, an H3K79 methyltransferase, is required for both initiation and maintenance of MLL-AF9-induced leukemogenesis in vitro and in vivo. Through gene expression and chromatin immunoprecipitation analysis we demonstrate that mistargeting of DOT1L, subsequent H3K79 methylation, and up-regulation of Hoxa and Meis1 genes underlie the molecular mechanism of how DOT1L contributes to MLL-AF9-mediated leukemogenesis. Our study not only provides the first in vivo evidence for the function of DOT1L in leukemia, but also reveals the molecular mechanism for DOT1L in MLL-AF9 mediated leukemia. Thus, DOT1L may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations.
authors.affiliation: Howard Hughes Medical Institute, Chapel Hill, NC, USA.
authors.forename: Anh Tram
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Olena
authors.initials: O
authors.lastname: Taranova
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; C489902:Mllt3 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; C481527:Dot1l protein, mouse; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase