Salmanidis, M.Brumatti, G.Narayan, N.Green, B.van den Bergen, J.Sandow, J.Bert, A.Silke, N.Sladic, R.Puthalakath, H.Rohrbeck, L.Okamoto, T.Bouillet, P.Herold, M.Goodall, G.Jabbour, A.Ekert, P.2013-11-272013-11-272013Cell Death and Differentiation, 2013; 20(10):1370-13801350-90471476-5403http://hdl.handle.net/2440/81313Hoxb8 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.en© 2013 Macmillan Publishers Limited All rights reservedApoptosisHoxb8interleukin-3microRNAJournal article002013174210.1038/cdd.2013.920003243017000122-s2.0-8488379880218076Goodall, G. [0000-0003-1294-0692]