title: ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia.
abstract: Numerous studies in multiple systems support that histone H3 lysine 36 dimethylation (H3K36me2) is associated with transcriptional activation; however, the underlying mechanisms are not well defined. Here, we show that the H3K36me2 chromatin mark written by the ASH1L histone methyltransferase is preferentially bound in vivo by LEDGF, a mixed-lineage leukemia (MLL)-associated protein that colocalizes with MLL, ASH1L, and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild-type MLL proteins to chromatin at key leukemia target genes and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely, KDM2A, an H3K36me2 demethylase and Polycomb group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies are the first to provide a basic mechanistic insight into epigenetic interactions wherein placement, interpretation, and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a novel target for therapeutic intervention.
  
  
  
  Epigenetic regulators play vital roles in cancer pathogenesis and represent a new frontier in therapeutic targeting. Our studies provide basic mechanistic insight into the role of H3K36me2 in transcription activation and MLL leukemia pathogenesis and implicate ASH1L histone methyltransferase as a promising target for novel molecular therapy. Cancer Discov; 6(7); 770-83. ©2016 AACR.See related commentary by Balbach and Orkin, p. 700This article is highlighted in the In This Issue feature, p. 681.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Stephen H K
authors.initials: SH
authors.lastname: Wong
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Brianna J
authors.initials: BJ
authors.lastname: Klein
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Larissa
authors.initials: L
authors.lastname: Ikenouye
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Onishi
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schneidawind
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Corina
authors.initials: C
authors.lastname: Buechele
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California.
authors.forename: Loren
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Jesús
authors.initials: J
authors.lastname: Duque-Afonso
authors.affiliation: Departments of Pathology and Developmental Biology, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Biology, Stanford University, Stanford, California.
authors.forename: Gloria Mas
authors.initials: GM
authors.lastname: Martin
authors.affiliation: Department of Biology, Stanford University, Stanford, California.
authors.forename: Or
authors.initials: O
authors.lastname: Gozani
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California. mcleary@stanford.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D064593:Heterografts; D059014:High-Throughput Nucleotide Sequencing; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D009707:Nucleosomes; D014157:Transcription Factors; C119380:lens epithelium-derived growth factor; D051788:Myeloid-Lymphoid Leukemia Protein; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D000076983:Histone Methyltransferases; C490911:ASH1L protein, human; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine