title: Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond.
abstract: Leukemias harboring mixed-lineage leukemia gene (MLL1) abnormalities are associated with poor clinical outcomes, and new therapeutic approaches are desperately needed. Rearrangement of the MLL1 gene generates chimeric proteins that fuse the NH3 terminus of MLL1 to the COOH terminus of its translocation partners. These MLL1 fusion oncoproteins drive the expression of homeobox genes such as HOXA cluster genes and myeloid ecotropic viral integration site 1 homolog (MEIS1), which are known to induce leukemic transformation of hematopoietic progenitors. Genomewide histone methylation studies have revealed that the abnormal expression of MLL1 fusion target genes is associated with high levels of H3K79 methylation at these gene loci. The only known enzyme that catalyzes methylation of H3K79 is disruptor of telomeric-silencing 1-like (DOT1L). Loss-of-function mouse models, as well as small molecular inhibitors of DOT1L, illustrate that leukemias driven by MLL1 translocations are dependent on DOT1L enzymatic activity for proliferation and for the maintenance of HOXA gene expression. Furthermore, DOT1L also appears to be important for HOXA gene expression in other settings including leukemias with select genetic abnormalities. These discoveries have established a foundation for disease-specific therapies that target chromatin modifications in highly malignant leukemias harboring specific genetic abnormalities. This review focuses on the molecular mechanisms underlying MLL1 translocation-driven leukemogenesis and the latest progress on DOT1L-targeted epigenetic therapies for MLL1-rearranged and other leukemias.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: Armstros@mskcc.org.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase