miR17~92 restrains pro-apoptotic BIM to ensure survival of haematopoietic stem and progenitor cells

Kerstin Brinkmann, Ashley P. Ng, Carolyn A. de Graaf, Ladina Di Rago, Craig D. Hyland, Eugenio Morelli, Jai Rautela, Nicholas D. Huntington, Andreas Strasser, Warren S. Alexander, Marco J. Herold

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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 languageEnglish
Pages (from-to)1475-1488
Number of pages14
JournalCell Death and Differentiation
Volume27
Issue number5
DOIs
Publication statusPublished - May 2020

Cite this

Brinkmann, K., Ng, A. P., de Graaf, C. A., Di Rago, L., Hyland, C. D., Morelli, E., Rautela, J., Huntington, N. D., Strasser, A., Alexander, W. S., & Herold, M. J. (2020). miR17~92 restrains pro-apoptotic BIM to ensure survival of haematopoietic stem and progenitor cells. Cell Death and Differentiation, 27(5), 1475-1488. https://doi.org/10.1038/s41418-019-0430-6