title: A HIF-1 network reveals characteristics of epithelial-mesenchymal transition in acute promyelocytic leukemia.
abstract: BACKGROUND
  Acute promyelocytic leukemia (APL) is a sub-type of acute myeloid leukemia (AML) characterized by a block of myeloid differentiation at the promyelocytic stage and the predominant t(15:17) chromosomal translocation. We have previously determined that cells from APL patients show increased expression of genes regulated by hypoxia-inducible transcription factors (HIFs) compared to normal promyelocytes. HIFs regulate crucial aspects of solid tumor progression and are currently being implicated in leukemogenesis.
  
  
  METHODS
  To investigate the contribution of hypoxia-related signaling in APL compared to other AML sub-types, we reverse engineered a transcriptional network from gene expression profiles of AML patients' samples, starting from a list of direct target genes of HIF-1. A HIF-1-dependent subnetwork of genes specifically dysregulated in APL was derived from the comparison between APL and other AMLs.
  
  
  RESULTS
  Interestingly, this subnetwork shows a unique involvement of genes related to extracellular matrix interaction and cell migration, with decreased expression of genes involved in cell adhesion and increased expression of genes implicated in motility and invasion, thus unveiling the presence of characteristics of epithelial-mesenchymal transition (EMT). We observed that the genes of this subnetwork, whose dysregulation shows a peculiar pattern across different AML sub-types, distinguish malignant from normal promyelocytes, thus ruling out dependence on a myeloid developmental stage. Also, expression of these genes is reversed upon treatment of APL-derived NB4 cells with all-trans retinoic acid and cell differentiation.
  
  
  CONCLUSIONS
  Our data suggest that pathways related to EMT-like processes can be implicated also in hematological malignancies besides solid tumors, and can identify specific AML sub-types.
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, piazza Leonardo da Vinci 32, 20133 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Percio
authors.affiliation: Division of Molecular Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy ; Leukemia Unit, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Coltella
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, piazza Leonardo da Vinci 32, 20133 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Grisanti
authors.affiliation: Division of Molecular Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy ; Leukemia Unit, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bernardi
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, piazza Leonardo da Vinci 32, 20133 Milan, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Pattini