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

An De Weer UGent, Joni Van der Meulen UGent, Pieter Rondou UGent, Tom Taghon UGent, Torsten A Konrad, Katleen De Preter UGent, Pieter Mestdagh UGent, Tom Van Maerken UGent, Nadine Van Roy UGent and Marta Jeison, et al. (2011) BRITISH JOURNAL OF HAEMATOLOGY. 154(3). p.337-348
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MECOM, EVI1, BCL2, HEMATOPOIETIC STEM-CELLS, DE-NOVO AML, MIR449A, NOTCH, ACUTE MYELOID-LEUKEMIA, MIRNA EXPRESSION, MICRORNA EXPRESSION, PCR DATA, GENE, CANCER, LINE, NOTCH
journal title
BRITISH JOURNAL OF HAEMATOLOGY
Br. J. Haematol.
volume
154
issue
3
pages
337 - 348
Web of Science type
Article
Web of Science id
000292648000007
JCR category
HEMATOLOGY
JCR impact factor
4.941 (2011)
JCR rank
13/68 (2011)
JCR quartile
1 (2011)
ISSN
0007-1048
DOI
10.1111/j.1365-2141.2011.08737.x
project
Bioinformatics: from nucleotids to networks (N2N)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2009521
handle
http://hdl.handle.net/1854/LU-2009521
date created
2012-01-31 12:22:50
date last changed
2013-02-27 09:11:17
@article{2009521,
  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.},
  author       = {De Weer, An and Van der Meulen, Joni and Rondou, Pieter and Taghon, Tom and Konrad, Torsten A and De Preter, Katleen and Mestdagh, Pieter and Van Maerken, Tom and Van Roy, Nadine and Jeison, Marta and Yaniv, Isaac and Cauwelier, Barbara and Noens, Lucien and Poirel, H{\'e}l{\`e}ne-Antoine and Vandenberghe, Peter and Lambert, Fr{\'e}d{\'e}ric and De Paepe, Anne and Garc{\'i}a S{\'a}nchez, Maria and Odero, Maria and Verhasselt, Bruno and Philipp{\'e}, Jan and Vandesompele, Jo and Wieser, Rotraud and Dastugue, Nicole and Van Vlierberghe, Pieter and Poppe, Bruce and Speleman, Franki},
  issn         = {0007-1048},
  journal      = {BRITISH JOURNAL OF HAEMATOLOGY},
  keyword      = {MECOM,EVI1,BCL2,HEMATOPOIETIC STEM-CELLS,DE-NOVO AML,MIR449A,NOTCH,ACUTE MYELOID-LEUKEMIA,MIRNA EXPRESSION,MICRORNA EXPRESSION,PCR DATA,GENE,CANCER,LINE,NOTCH},
  language     = {eng},
  number       = {3},
  pages        = {337--348},
  title        = {EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells},
  url          = {http://dx.doi.org/10.1111/j.1365-2141.2011.08737.x},
  volume       = {154},
  year         = {2011},
}

Chicago
De Weer, An, Joni Van der Meulen, Pieter Rondou, Tom Taghon, Torsten A Konrad, Katleen De Preter, Pieter Mestdagh, et al. 2011. “EVI1-mediated down Regulation of MIR449A Is Essential for the Survival of EVI1 Positive Leukaemic Cells.” British Journal of Haematology 154 (3): 337–348.
APA
De Weer, An, Van der Meulen, J., Rondou, P., Taghon, T., Konrad, T. A., De Preter, K., Mestdagh, P., et al. (2011). EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells. BRITISH JOURNAL OF HAEMATOLOGY, 154(3), 337–348.
Vancouver
1.
De Weer A, Van der Meulen J, Rondou P, Taghon T, Konrad TA, De Preter K, et al. EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells. BRITISH JOURNAL OF HAEMATOLOGY. 2011;154(3):337–48.
MLA
De Weer, An, Joni Van der Meulen, Pieter Rondou, et al. “EVI1-mediated down Regulation of MIR449A Is Essential for the Survival of EVI1 Positive Leukaemic Cells.” BRITISH JOURNAL OF HAEMATOLOGY 154.3 (2011): 337–348. Print.