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

Br J Haematol 2011 Aug 14;154(3):337-48. Epub 2011 May 14.

Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

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.

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http://dx.doi.org/10.1111/j.1365-2141.2011.08737.xDOI Listing
August 2011
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References

(Supplied by CrossRef)
The role of EVI1 in normal and leukemic cells
Buonamici et al.
Blood cells, molecules & diseases 2003
Methylation and silencing of miRNA-124 by EVI1 and self-renewal exhaustion of hematopoietic stem cells in murine myelodysplastic syndrome
Dickstein et al.
Proceedings of the National Academy of Sciences of the United States of America 2010
Is the cancer stem cell population “a player” in multi-drug resistance?
Drewa et al.
Acta Poloniae Pharmaceutica 2008

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