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

Cell Death Differ. 2020 May;27(5):1475-1488. doi: 10.1038/s41418-019-0430-6. Epub 2019 Oct 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Apoptosis* / genetics
  • Bcl-2-Like Protein 11 / metabolism*
  • Cell Survival / genetics
  • Female
  • Gene Deletion
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*

Substances

  • Antigens, CD34
  • Bcl-2-Like Protein 11
  • MIRN17-92 microRNA, mouse
  • MicroRNAs