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

Adult; Aged; Aged, 80 and over; Apoptosis/genetics; Cell Survival; DNA-Binding Proteins/metabolism/physiology; Down-Regulation/physiology; Gene Expression Profiling/methods; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Infant; Leukemia/genetics/metabolism/pathology; MicroRNAs/biosynthesis/genetics; Middle Aged; Proto-Oncogene Proteins c-bcl-2/biosynthesis/physiology; Proto-Oncogenes/physiology; RNA, Neoplasm/genetics; Receptor, Notch1/biosynthesis/physiology; Regulatory Elements, Transcriptional/physiology; Transcription Factors/metabolism/physiology; Tumor Cells, Cultured

Abstract :

[en] 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.

Disciplines :

Genetics & genetic processes

Author, co-author :

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

More authors (17 more)

Language :

English

Title :

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

Publication date :

2011

Journal title :

British Journal of Haematology

ISSN :

0007-1048

eISSN :

1365-2141

Publisher :

Blackwell Publishing, Oxford, United Kingdom

Volume :

154

Issue :

Pages :

337-48

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 27 January 2012

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