title: EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells.
abstract: Chromosomal rearrangements involving the MECOM (MDS1 and EVI1 complex) locus are recurrent genetic events in myeloid leukaemia and are associated with poor prognosis. In this study, we assessed the role of MECOM locus protein EVI1 in the transcriptional regulation of microRNAs (miRNAs) involved in the leukaemic phenotype. For this, we profiled expression of 366 miRNAs in 38 MECOM-rearranged patient samples, normal bone marrow controls and MECOM (EVI1) knock down/re-expression models. Cross-comparison of these miRNA expression profiling data showed that MECOM rearranged leukaemias are characterized by down regulation of MIR449A. Reconstitution of MIR449A expression in MECOM-rearranged cell line models induced apoptosis resulting in a strong decrease in cell viability. These effects might be mediated in part by MIR449A regulation of NOTCH1 and BCL2, which are shown here to be bona fide MIR449A targets. Finally, we confirmed that MIR449A repression is mediated through direct promoter occupation of the EVI1 transcriptional repressor. In conclusion, this study reveals MIR449A as a crucial direct target of the MECOM locus protein EVI1 involved in the pathogenesis of MECOM-rearranged leukaemias and unravels NOTCH1 and BCL2 as important novel targets of MIR449A. This EVI1-MIR449A-NOTCH1/BCL2 regulatory axis might open new possibilities for the development of therapeutic strategies in this poor prognostic leukaemia subgroup.
authors.affiliation: Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: De Weer
authors.forename: Joni
authors.initials: J
authors.lastname: Van der Meulen
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.forename: Torsten A
authors.initials: TA
authors.lastname: Konrad
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.forename: Tom
authors.initials: T
authors.lastname: Van Maerken
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.forename: Marta
authors.initials: M
authors.lastname: Jeison
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Barbara
authors.initials: B
authors.lastname: Cauwelier
authors.forename: Lucien
authors.initials: L
authors.lastname: Noens
authors.forename: Hélène-Antoine
authors.initials: HA
authors.lastname: Poirel
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lambert
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Maria García
authors.initials: MG
authors.lastname: Sánchez
authors.forename: Maria
authors.initials: M
authors.lastname: Odero
authors.forename: Bruno
authors.initials: B
authors.lastname: Verhasselt
authors.forename: Jan
authors.initials: J
authors.lastname: Philippé
authors.forename: Joke
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Rotraud
authors.initials: R
authors.lastname: Wieser
authors.forename: Nicole
authors.initials: N
authors.lastname: Dastugue
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D011519:Proto-Oncogenes / Q000502:physiology*; D012334:RNA, Neoplasm / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000502:physiology; D050436:Regulatory Elements, Transcriptional / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012334:RNA, Neoplasm; D051881:Receptor, Notch1; D014157:Transcription Factors