EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells

An De Weer, Joni Van der Meulen, Pieter Rondou, Tom Taghon, Torsten A. Konrad, Katleen De Preter, Pieter Mestdagh, Tom Van Maerken, Nadine Van Roy, Marta Jeison, Isaac Yaniv, Barbara Cauwelier, Lucien Noens, Hélène Antoine Poirel, Peter Vandenberghe, Frédéric Lambert, Anne De Paepe, Maria García Sánchez, Maria Odero, Bruno VerhasseltJan Philippé, Joke Vandesompele, Rotraud Wieser, Nicole Dastugue, Pieter Van Vlierberghe, Bruce Poppe, Frank Speleman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)337-348
Number of pages12
JournalBritish Journal of Haematology
Volume154
Issue number3
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • BCL2
  • EVI1
  • MECOM
  • MIR449A
  • NOTCH

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