Title: EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells
Authors: De Weer, An ×
Van der Meulen, Joni
Rondou, Pieter
Taghon, Tom
Konrad, Torsten A
De Preter, Katleen
Mestdagh, Pieter
Van Maerken, Tom
Van Roy, Nadine
Jeison, Marta
Yaniv, Isaac
Cauwelier, Barbara
Noens, Lucien
Poirel, Hélène-Antoine
Vandenberghe, Peter
Lambert, Frédéric
De Paepe, Anne
Sánchez, Maria García
Odero, Maria
Verhasselt, Bruno
Philippé, Jan
Vandesompele, Joke
Wieser, Rotraud
Dastugue, Nicole
Van Vlierberghe, Pieter
Poppe, Bruce
Speleman, Frank #
Issue Date: May-2011
Publisher: Blackwell Scientific Publications
Series Title: British Journal of Haematology vol:154 issue:3 pages:337-348
Article number: 10.1111/j.1365-2141.2011.08737.x
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.
ISSN: 0007-1048
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
De Weer.pdfpublisher's version pdf Published 501KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science