title: Extracellular Histone Released from Leukemic Cells Increases Their Adhesion to Endothelium and Protects them from Spontaneous and Chemotherapy-Induced Leukemic Cell Death.
abstract: BACKGROUND
  When leukocytes are stimulated by reactive oxygen species (ROS), they release nuclear contents into the extracellular milieu, called by extracellular traps (ET). The nuclear contents are mainly composed of the histone-DNA complex and neutrophil elastase. This study investigated whether leukemic cells could release ET and the released histone could induce endothelial activation, eventually resulting in leukemic progression.
  
  
  METHODS
  The circulating ET were measured in 80 patients with hematologic diseases and 40 healthy controls. ET formation and ROS levels were investigated during leukemic cell proliferation in vitro. Histone-induced endothelial adhesion molecules expression and cell survival were measured by flow cytometry.
  
  
  RESULTS
  Acute leukemia patients had high levels of ET, which correlated with peripheral blast count. Leukemic cells produced high ROS levels and released extracellular histone, which was significantly blocked by antioxidants. Histone significantly induced 3 endothelial adhesion molecules expression, and promoted leukemic cell adhesion to endothelial cells, which was inhibited by histone inhibitors (heparin, polysialic acid, and activated protein C), neutralizing antibodies against these adhesion molecules, and a Toll like receptor(TLR)9 antagonist. When leukemic cells were co-cultured with endothelial cells, adherent leukemic cells showed better survival than the non-adherent ones, demonstrating that histone-treated endothelial cells protected leukemic cells from both spontaneous and chemotherapy-induced death.
  
  
  CONCLUSIONS
  Our data demonstrate for the first time that extracellular histone can be released from leukemic cells through a ROS-dependent mechanism. The released histone promotes leukemic cell adhesion by inducting the surface expression of endothelial adhesion molecules and eventually protects leukemic cells from cell death.
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jee-Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: JaYoon
authors.initials: J
authors.lastname: Gu
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Youngil
authors.initials: Y
authors.lastname: Koh
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D065206:Extracellular Traps / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D006657:Histones; D017382:Reactive Oxygen Species