title: Homeobox protein HB9 binds to the prostaglandin E receptor 2 promoter and inhibits intracellular cAMP mobilization in leukemic cells.
abstract: BACKGROUND
  HB9 is highly expressed in translocation t(7;12) positive infant AML.
  
  
  RESULTS
  HB9 binds to the PTGER2 promoter, down-regulates PTGER2 gene expression and subsequently represses cAMP synthesis in hematopoietic cells.
  
  
  CONCLUSIONS
  Expression of HLXB9 represses PTGER2 mediated signaling.
  
  
  CONCLUSIONS
  First molecular report of HB9-dependent target gene regulation in hematopoietic cells. The transcription factor HB9, encoded by the homeobox gene B9 (HLXB9), is involved in the development of pancreatic beta- and motor neuronal cells. In addition, HLXB9 is recurrently rearranged in young children with acute myeloid leukemia characterized by a chromosomal translocation t(7;12)-HLXB9/TEL and concomitant high expression of the unrearranged, wild-type HLXB9 allele. However, target genes of HB9 in hematopoietic cells are not known to date. In this study, we used ChIP-on-chip analysis together with expression profiling and identified PTGER2 (prostaglandin E receptor 2) as a target gene of HB9 in a hematopoietic cell line. The functional HB9 homeodomain as well as the HB9 binding domain within the PTGER2 promoter are essential for binding of HB9 to the PTGER2 promoter region and down-regulation of PTGER2 expression. Functionally, HB9 conducted down-regulation of PTGER2 results in a reduced content of intracellular cAMP mobilization and furthermore the decreased PTGER2 gene expression is valid in bone marrow cells from translocation t(7;12) positive patients. Among the primary and secondary target genes of HB9 in the myeloid cell line HL60, 78% of significantly regulated genes are down-regulated, indicating an overall repressive function of HB9. Differentially regulated genes were preferentially confined to pathways involved in cell-adhesion and cell-cell interactions, similar to the gene expression footprint of HLXB9-expressing cells from t(7;12) positive patients.
authors.affiliation: Department of Pediatric Oncology, Hematology, and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wildenhain
authors.forename: Deborah
authors.initials: D
authors.lastname: Ingenhag
authors.forename: Christian
authors.initials: C
authors.lastname: Ruckert
authors.forename: Özer
authors.initials: Ö
authors.lastname: Degistirici
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.forename: Roland
authors.initials: R
authors.lastname: Meisel
authors.forename: Julia
authors.initials: J
authors.lastname: Hauer
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
mesh_terms: D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C490003:MNX1 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D014157:Transcription Factors; D000242:Cyclic AMP