title: Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia.
abstract: Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mutAML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1mutAML to be exceptionally dependent on the menin binding site in MLL1. Pharmacologic small-molecule inhibition of the menin-MLL1 protein interaction had profound antileukemic activity in human and murine models of NPM1mutAML. Combined pharmacologic inhibition of menin-MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mutleukemia.
  
  
  
  MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1mutAML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. Cancer Discov; 6(10); 1166-81. ©2016 AACR.See related commentary by Hourigan and Aplan, p. 1087This article is highlighted in the In This Issue feature, p. 1069.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine III, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Michael W M
authors.initials: MW
authors.lastname: Kühn
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Song
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Amit
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Aniruddha J
authors.initials: AJ
authors.lastname: Deshpande
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Monica
authors.initials: M
authors.lastname: Cusan
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Noushin
authors.initials: N
authors.lastname: Farnoud
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mupo
authors.affiliation: Department of Haematology, PathWest/Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Grove
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Koche
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Antitumor Assessment Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: George S
authors.initials: GS
authors.lastname: Vassiliou
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hoshii
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. scott_armstrong@dfci.harvard.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D001665:Binding Sites; D064113:CRISPR-Cas Systems; D002843:Chromatin / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C105373:MEN1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3