title: EphB1 Suppression in Acute Myelogenous Leukemia: Regulating the DNA Damage Control System.
abstract: Loss of ephrin receptor (EphB1) expression may associate with aggressive cancer phenotypes; however, the mechanism of action remains unclear. To gain detailed insight into EphB1 function in acute myelogenous leukemia (AML), comprehensive analysis of EphB1 transcriptional regulation was conducted. In AML cells, EphB1 transcript was inversely correlated with EphB1 promoter methylation. The presence of EphB1 allowed EfnB1 ligand-mediated p53 DNA binding, leading to restoration of the DNA damage response (DDR) cascade by the activation of ATR, Chk1, p53, p21, p38, CDK1(tyr15), and Bax, and downregulation of HSP27 and Bcl2. Comparatively, reintroduction of EphB1 expression in EphB1-methylated AML cells enhanced the same cascade of ATR, Chk1, p21, and CDK1(tyr15), which consequently enforced programmed cell death. Interestingly, in pediatric AML samples, EphB1 peptide phosphorylation and mRNA expression were actively suppressed as compared with normal bone marrow, and a significant percentage of the primary AML specimens had EphB1 promoter hypermethylation. Finally, EphB1 repression associated with a poor overall survival in pediatric AML. Combined, the contribution of EphB1 to the DDR system reveals a tumor-suppressor function for EphB1 in pediatric AML.
  
  
  CONCLUSIONS
  The tumor-suppressor function of EphB1 is clinically relevant across many malignancies, suggesting that EphB1 is an important regulator of common cancer cell transforming pathways.
authors.affiliation: Department of Pediatric Oncology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: K R
authors.initials: KR
authors.lastname: Kampen
authors.affiliation: Department of Pediatric Oncology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: F J G
authors.initials: FJ
authors.lastname: Scherpen
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: G J L
authors.initials: GJ
authors.lastname: Kaspers
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Cloos
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: S M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Pediatric Oncology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. e.s.j.m.de.bont@umcg.nl.
authors.forename: E S J M
authors.initials: ES
authors.lastname: De Bont
mesh_terms: D017209:Apoptosis; D001853:Bone Marrow; D045744:Cell Line, Tumor; D002648:Child; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D015536:Down-Regulation; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D036082:Receptor, EphA1 / Q000378:metabolism; D036183:Receptor, EphB2 / Q000378:metabolism*
chemical_list: C586310:EPHB2 protein, human; D036082:Receptor, EphA1; D036183:Receptor, EphB2