Hoxb8 regulates expression of microRNAs to control cell death and differentiation Academic Article uri icon

abstract

  • Hoxb8 overexpression immortalises haematopoietic progenitor cells in a growth-factor-dependant manner and co-operates with interleukin-3 (IL-3) to cause acute myeloid leukaemia. To further understand how Hoxb8 contributes to myeloid cell immortalisation, we generated IL-3-dependant myeloid cells expressing Hoxb8 under the control of an inducible promoter. Downregulation of Hoxb8, in the presence of IL-3, caused cell-cycle arrest and apoptosis in the majority of cells. Apoptosis was dependant on Bax and Bak and, in part, on Bim, which was repressed by Hoxb8. Deletion of the miR-17∼92 seed sequences in the Bim 3'UTR abolished Hoxb8-dependant regulation of Bim reporter constructs. Expression of all six miRNAs from this cluster were elevated when Hoxb8 was overexpressed. The miR-17∼92 cluster was required for repression of Bim in Hoxb8-immortalised cells and deletion of the miR-17∼92 cluster substantially inhibited Hoxb8, but not Hoxa9, mediated survival and proliferation. Hoxb8 appears to promote miR-17∼92 expression through c-Myc, a known transcriptional regulator of the miR-17∼92 cluster. We have uncovered a previously unrecognised link between Hoxb8 expression and microRNAs that provides a new insight into the oncogenic functions of Hoxb8.

authors

  • Salmanidis, M
  • Brumatti, G
  • Narayan, N
  • Green, BD
  • van den Bergen, JA
  • Sandow, JJ
  • Bert, AG
  • Silke, N
  • Sladic, R
  • Puthalakath, H
  • Rohrbeck, L
  • Okamoto, T
  • Bouillet, P
  • Herold, MJ
  • Goodall, GJ
  • Jabbour, AM
  • Ekert, PG

publication date

  • October 2013

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