title: YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway.
abstract: BACKGROUND
  Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL.
  
  
  METHODS
  Primary ALL samples and ALL cell lines were interrogated with YM155 to identify drug sensitivity. Ph(+)ALL harboring the BCR-ABL1 oncogene were tested for any interaction with YM155 and the multi-kinase inhibitor dasatinib. Representative ALL cell lines were tested to identify the response to YM155 using standard biochemical assays as well as RNA expression and phosphorylation arrays.
  
  
  RESULTS
  ALL samples exhibited significant sensitivity to YM155, and an additive response was observed with dasatinib in the setting of Ph(+)ALL. ALL cells were more sensitive to YM155 during S phase during DNA replication. YM155 activates the DNA damage pathway leading to phosphorylation of Chk2 and H2AX. Interestingly, screening of primary patient samples identified unique and exquisite YM155 sensitivity in some but not all ALL specimens.
  
  
  CONCLUSIONS
  These results are the first to have screened a large number of primary patient leukemic samples to identify individual variations of response to YM155. Our studies further support that YM155 in ALL induces DNA damage leading to S phase arrest. Finally, only subsets of ALL have exquisite sensitivity to YM155 presumably through both suppression of survivin expression and activation of the DNA damage pathway underscoring its potential for therapeutic development.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA. changb@ohsu.edu.|OHSU Knight Cancer Institute, Portland, OR, 97239, USA. changb@ohsu.edu.
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. johnskar@ohsu.edu.
authors.forename: Kara
authors.initials: K
authors.lastname: Johnson
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. dhl89@cornell.edu.
authors.forename: Dorian
authors.initials: D
authors.lastname: LaTocha
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. rowleyj@ohsu.edu.
authors.forename: Joelle S J
authors.initials: JS
authors.lastname: Rowley
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. JADE.BRYANT@UCDENVER.EDU.
authors.forename: Jade
authors.initials: J
authors.lastname: Bryant
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. Russell.Burke@Colorado.EDU.
authors.forename: Russell
authors.initials: R
authors.lastname: Burke
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. smithreb@ohsu.edu.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Smith
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. loriauxm@ohsu.edu.|Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA. loriauxm@ohsu.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Loriaux
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA. Markus.Muschen@ucsf.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital and University of Tennessee Health Science Center, Memphis, TN, 38105, USA. Charles.Mullighan@STJUDE.ORG.
authors.forename: Charles
authors.initials: C
authors.lastname: Mullighan
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. drukerb@ohsu.edu.|Howard Hughes Medical Institute, Portland, OR, 97239, USA. drukerb@ohsu.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: OHSU Knight Cancer Institute, Portland, OR, 97239, USA. tynerj@ohsu.edu.|Department Cell & Developmental Biology, Oregon Health & Science University, Portland, OR, 97239, USA. tynerj@ohsu.edu.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D009285:Naphthoquinones / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D009285:Naphthoquinones; C523798:sepantronium