title: Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma.
abstract: OBJECTIVE
  Approximately 50% of patients with diffuse large B-cell lymphoma (DLBCL) enter long-term remission after standard chemotherapy. Patients with DLBCL who do not respond to chemotherapy have few treatment options. There remains a critical need to identify effective and targeted therapeutics for DLBCL.
  
  
  METHODS
  Recent studies have highlighted the incidence of increased c-MYC protein in DLBCL and the correlation between high levels of c-MYC protein and poor survival prognosis of patients with DLBCL, suggesting that c-MYC is a compelling target for DLBCL therapy. The small molecule JQ1 suppresses c-MYC expression through inhibition of the bromodomain and extra-terminal (BET) family of bromodomain proteins. We investigated whether JQ1 can inhibit proliferation of DLBCL cells in culture and xenograft models in vivo.
  
  
  RESULTS
  We show that JQ1 at nanomolar concentrations efficiently inhibited proliferation of human DLBCL cells in a dose-dependent manner regardless of their molecular subtypes, suggesting a broad effect of JQ1 in DLBCL. The initial G1 arrest induced by JQ1 treatment in DLBCL cells was followed by either apoptosis or senescence. The expression of c-MYC was suppressed as a result of JQ1 treatment from the natural, chromosomally translocated, or amplified loci. Furthermore, JQ1 treatment significantly suppressed growth of DLBCL cells engrafted in mice and improved survival of engrafted mice.
  
  
  CONCLUSIONS
  Our results demonstrate that inhibition of the BET family of bromodomain proteins by JQ1 has potential clinical use in the treatment of DLBCL.
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Trabucco
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Gerstein
authors.affiliation: Division of Hematology and Oncology, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Evens
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts. hong.zhang@umassmed.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles