title: miR-155 regulative network in FLT3 mutated acute myeloid leukemia.
abstract: BACKGROUND
  Acute myeloid leukemia (AML) represents a heterogeneous disorder with recurrent chromosomal alterations and molecular abnormalities. Among AML with normal karyotype (NK-AML) FLT3 activating mutation, internal tandem duplication (FLT3-ITD), is present in about 30% of patients, conferring unfavorable outcome. Our previous data demonstrated specific up-regulation of miR-155 in FLT3-ITD+ AML. miR-155 is known to be directly implicated in normal hematopoiesis and in some pathologies such as myeloid hyperplasia and acute lymphoblastic leukemia.
  
  
  RESULTS
  To investigate about the potential influence of miR-155 de-regulation in FLT3-mutated AML we generated a transcription factors regulatory network and combined this with data from multiple sources that predict miR-155 interactions. From these analyses, we derived a sub-network, called "miR-155 module" that describes functional relationship among miR-155 and transcription factors in FLT3-mutated AML. We found that "miR-155 module" is characterized by the presence of six transcription factors as central hubs: four miR-155 regulators (JUN, RUNX1, FOSb, JUNB) and two targets of miR-155 (SPI1, CEBPB) all known to be "master" genes of myelopoiesis. We found, in FLT3-mutated AML, a significant down-regulation of miR-155 target genes CEBPB and SPI1 and up-regulation of miR-155 regulator genes JUN and RUNX1. We also showed that PKC412-related FLT3 inhibition, in MV4-11 cell line, causes down-regulation of miR-155 and increased level of mRNA and protein of miR-155 target SPI1. We showed in experiments of miR-155 mimic in K562 cell line, a high increase of miR-155 and an inverse correlation with the mRNA levels of its targets SPI1 and CEBPB. Moreover silencing of miR-155 in primary AMLs causes mRNA up-regulation of its target SPI1 and CEBPB.
  
  
  CONCLUSIONS
  Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation.
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Salemi
authors.affiliation: IBIM CNR, Palermo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cammarata
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Agueli
authors.affiliation: Dipartimento di Scienze Statistiche e Matematiche "Silvio Vianelli," Università di Palermo, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Augugliaro
authors.affiliation: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Sezione di Biologia e Genetica, Palermo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Corrado
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Bica
authors.affiliation: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Sezione di Biologia e Genetica, Palermo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Raimondo
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Marfia
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Randazzo
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dragotto
authors.affiliation: Divisione di Ematologia, P.O. Ferrarotto Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.affiliation: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Sezione di Biologia e Genetica, Palermo, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Alessandro
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbiano
authors.affiliation: Divisione di Ematologia con UTMO, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy. Electronic address: a.santoro@villasofia.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Santoro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: AML; MicroRNA; Network