title: PML-RAR alpha induces the downmodulation of HHEX: a key event responsible for the induction of an angiogenetic response.
abstract: BACKGROUND
  Recent studies indicate that angiogenesis is important in the pathogenesis of acute myeloid leukemias (AMLs). Among the various AMLs, the bone marrow angiogenetic response is particularly pronounced in acute promyelocytic leukemia (APL). However, the molecular mechanisms responsible for this angiogenetic response are largely unknown. In the present study, we have explored the role of HHEX, a homeodomain transcription factor, as a possible mediator of the pro-angiogenetic response observed in APL. This transcription factor seems to represent an ideal candidate for this biologic function because it is targeted by PML-RARα, is capable of interaction with PML and PML-RARα, and acts as a regulator of the angiogenetic response.
  
  
  METHODS
  We used various cellular systems of APL, including primary APL cells and leukemic cells engineered to express PML-RARα, to explore the role of the PML-RARα fusion protein on HHEX expression. Molecular and biochemical techniques have been used to investigate the mechanisms through which PML-RARα downmodulates HHEX and the functional consequences of this downmodulation at the level of the expression of various angiogenetic genes, cell proliferation and differentiation.
  
  
  RESULTS
  Our results show that HHEX expression is clearly downmodulated in APL and that this effect is directly mediated by a repressive targeting of the HHEX gene promoter by PML-RARα. Studies carried out in primary APL cells and in a cell line model of APL with inducible PML-RARα expression directly support the view that this fusion protein through HHEX downmodulation stimulates the expression of various genes involved in angiogenesis and inhibits cell differentiation.
  
  
  CONCLUSIONS
  Our data suggest that HHEX downmodulation by PML-RARα is a key event during APL pathogenesis.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Saulle
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Petronelli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Pelosi
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Coppotelli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pasquini
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Ilari
authors.affiliation: Department of Biomedicine and Prevention, University of Rome "Tor Vergata" and Fondazione Santa Lucia, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. ugo.testa@iss.it.
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C078492:HHEX protein, human; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D040301:Vascular Endothelial Growth Factor Receptor-2