title: Disturbing the histone code in leukemia: translocations and mutations affecting histone methyl transferases.
abstract: Leukemia is characterized by increased numbers of blasts originating from transformed early hematopoietic stem and progenitor cells. Genetic alterations are widely recognized as the main drivers of oncogenic transformation. Of considerable interest are mutations affecting the writers of epigenetic marks. In this review, we focus on histone methyltransferases--enzymes that catalyze the methylation of lysine residues in core histones. Histone methylation is a tightly controlled mechanism that is responsible for both activating as well as repressing gene expression in a site-specific manner, depending on which lysine residue is methylated. Histone methyltransferases, including MLL1, DOT1L, EZH2, and SETD2 are recurrently deregulated in human leukemia, either directly by gene mutations or balanced translocations, or indirectly as components of protein complexes that are disturbed in leukemia due to alterations of the other components in these complexes. Several small molecule inhibitors of histone methyltransferases are currently being clinically evaluated for their therapeutic potential in human leukemia. These drugs reverse some of the adverse effects of aberrant histone methylation, and can induce differentiation and cell death in leukemic blasts.
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: Martin
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. Electronic address: s.bohlander@auckland.ac.nz.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics*; D008239:Lysine / Q000737:chemistry; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; C473477:DOT1L protein, human; D000076983:Histone Methyltransferases; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C521636:SETD2 protein, human; D008239:Lysine
keywords: Cancer; epigenetics; histone methylation; histone methyltransferases; leukemia