EVI1 mediated down regulation of miR-449a is essential for the survival of EVI1 positive leukemic cells

An de Weer (1) , Joni van Der Meulen (1) , Pieter Rondou (1) , Tom Taghon (2) , Torsten Konrad (3) , Katleen de Preter (1) , Pieter Mestdagh (1) , Tom van Maerken (1) , Nadine van Roy (1) , Marta Jeison (4) , Isaac Yaniv (4) , Barbara Cauwelier (5) , Lucien Noens (6) , Hélène Poirel (7) , Peter Vandenberghe (8) , Frédéric Claude Daniel Lambert (9) , Maria A Garcia-Sanchez (10) , Maria D Odero (11) , Pieter van Vlierberghe (1) , Frank Speleman (1)

1 Center for Medical Genetics [Ghent]
2 Department of Clinical Chemistry, Microbiology and Immunology
3 Department of Medical Genetics
4 Department of Pediatric Hematology Oncology
5 Department of Hematology
6 Department of Hematology
7 Human Molecular Genetics
8 Haematology
9 Medical Genetics
10 Division of Oncology
11 Genetics

Chromosomal rearrangements involving the Ecotropic Viral Integration site 1 (EVI1) locus are recurrent genetic events in myeloid leukemia and are associated with poor prognosis. In this study, we assessed the role of EVI1 in the transcriptional regulation of microRNAs (miRNAs) involved in the leukemic phenotype. For this, we profiled expression of 366 miRNAs in 38 EVI1 rearranged patient samples, normal bone marrow controls and EVI1 knock down/re-expression models. Cross-comparison of these miRNA expression profiling data showed that EVI1 rearranged leukemias are characterized by down regulation of miR-449a. Reconstitution of miR-449a expression in EVI1 rearranged cell line models induced apoptosis resulting in a strong decrease in cell viability. These effects might be mediated in part by miR-449a regulation of NOTCH1 and BCL2 which are shown here to be bona fide miR-449a targets. Finally, we confirmed that miR-449a repression is mediated through direct promoter occupation of the EVI1 transcriptional repressor. In conclusion, this study reveals miR-449a as a crucial direct target of EVI1 involved in the pathogenesis of EVI1 rearranged leukemias and unravels NOTCH1 and BCL2 as important novel targets of miR-449a. This EVI1-miR-449a-NOTCH1/BCL2 regulatory axis might open new possibilities for the development of therapeutic strategies in this poor prognostic leukemia subgroup.

Mots clés: Medicine

An de Weer, Joni van Der Meulen, Pieter Rondou, Tom Taghon, Torsten Konrad, et al.. EVI1 mediated down regulation of miR-449a is essential for the survival of EVI1 positive leukemic cells. British Journal of Haematology, 2011, 154 (3), pp.337. ⟨10.1111/j.1365-2141.2011.08737.x⟩. ⟨hal-00640631⟩