title: Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia.
abstract: BACKGROUND
  Mixed lineage leukemia (MLL) gene translocations are found in ~75% infant and 10% adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be a drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL-rearranged leukemia are needed.
  
  
  METHODS
  LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells.
  
  
  RESULTS
  Potent LSD1 inhibitors with biochemical IC50 values of 9.8-77 nM were found to strongly inhibit proliferation of MLL-rearranged leukemia cells with EC50 of 10-320 nM, while these compounds are generally non-cytotoxic to several other tumor cells. LSD1 inhibition increased histone H3 lysine 4 (H3K4) methylation, downregulated expression of several leukemia-relevant genes, induced apoptosis and differentiation, and inhibited self-renewal of stem-like leukemia cells. Moreover, LSD1 inhibitors worked synergistically with inhibition of DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, against MLL-rearranged leukemia. The most potent LSD1 inhibitor showed significant in vivo activity in a systemic mouse model of MLL-rearranged leukemia without overt toxicities. Mechanistically, LSD1 inhibitors caused significant upregulation of several pathways that promote hematopoietic differentiation and apoptosis.
  
  
  CONCLUSIONS
  LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Fangrui
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.|Texas Children's Cancer and Hematology Centers, 1102 Bates Street, Houston, TX, 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.|Texas Children's Cancer and Hematology Centers, 1102 Bates Street, Houston, TX, 77030, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Redell
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.|Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. ysong@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. ysong@bcm.edu.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002648:Child; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015321:Gene Rearrangement; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; C497422:KMT2A protein, human; D008996:Monoamine Oxidase Inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein; D056466:Histone Demethylases; C495195:KDM1A protein, human; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
keywords: Drug discovery; Enzyme inhibitor; Leukemia therapeutics; Lysine-specific demethylase 1; MLL-rearranged leukemia