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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) , Marta Jeison, et al.
(2011) BRITISH JOURNAL OF HAEMATOLOGY. 154(3). p.337-348
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Bioinformatics: from nucleotids to networks (N2N)
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.
Keywords
MECOM, EVI1, BCL2, HEMATOPOIETIC STEM-CELLS, DE-NOVO AML, MIR449A, NOTCH, ACUTE MYELOID-LEUKEMIA, MIRNA EXPRESSION, MICRORNA EXPRESSION, PCR DATA, GENE, CANCER, LINE, NOTCH

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Citation

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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.
@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},
  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},
}

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