Hoxb8 regulates expression of microRNAs to control cell death and differentiation

Marika Salmanidis, Gabriela Brumatti, Nisha Narayan, Benjamin D Green, Jocelyn A van den Bergen, Jarrod J Sandow, Andrew G Bert, Natasha Silke, Rosemary Sladic, Hamsa Puthalakath, Leona Rohrbeck, Toru Okamoto, Phillipe Bouillet, Marco J Herold, Gregory John Goodall, Anissa Jabbour, Paul G Ekert

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1370 - 1380
Number of pages11
JournalCell Death and Differentiation
Volume20
Issue number10
DOIs
Publication statusPublished - 2013
Externally publishedYes

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