Projects per year
Abstract
The miR17~92 cluster plays important roles in haematopoiesis. However, it is not clear at what stage of differentiation and through which targets miR17~92 exerts this function. Therefore, we generated miR17~92fl/fl; RosaCreERT2 mice for inducible deletion of miR17~92 in haematopoietic cells. Bone marrow reconstitution experiments revealed that miR17~92-deleted cells were not capable to contribute to mature haematopoietic lineages, which was due to defects in haematopoietic stem/progenitor cells (HSPCs). To identify the critical factor targeted by miR17~92 we performed gene expression analysis in HSPCs, demonstrating that mRNA levels of pro-apoptotic Bim inversely correlated with the expression of the miR17~92 cluster. Strikingly, loss of pro-apoptotic BIM completely prevented the loss of HSPCs caused by deletion of miR17~92. The BIM/miR17~92 interaction is conserved in human CD34+ HSPCs, as miR17~92 inhibition or blockade of its binding to the BIM 3′UTR reduced the survival and growth of these cells. Despite the prediction that miR17~92 functions by impacting a plethora of different targets, the absence of BIM alone is sufficient to prevent all defects caused by deletion of miR17~92 in haematopoietic cells.
Original language | English |
---|---|
Pages (from-to) | 1475-1488 |
Number of pages | 14 |
Journal | Cell Death and Differentiation |
Volume | 27 |
Issue number | 5 |
DOIs | |
Publication status | Published - May 2020 |
Projects
- 2 Finished
-
Identification and targeting of a potent NK cell “checkpoint” in tumour immunity
Huntington, N. (Primary Chief Investigator (PCI))
National Health and Medical Research Council (NHMRC) (Australia)
1/02/19 → 31/12/20
Project: Research
-
Apoptosis and stem cells in cancer development and therapy
Gerondakis, S. (Primary Chief Investigator (PCI)), Adams, J. M. (Chief Investigator (CI)), Bouillet, P. (Chief Investigator (CI)), Colman, P. G. (Chief Investigator (CI)), Cory, S. (Chief Investigator (CI)), Huang, D. (Chief Investigator (CI)), Kluck, R. (Chief Investigator (CI)), Lindeman, G. (Chief Investigator (CI)), Strasser, A. (Chief Investigator (CI)), Vaux, D. (Chief Investigator (CI)) & Visvader, J. E. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/12 → 31/12/16
Project: Research