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

18 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

Cite this

Salmanidis, M., Brumatti, G., Narayan, N., Green, B. D., van den Bergen, J. A., Sandow, J. J., ... Ekert, P. G. (2013). Hoxb8 regulates expression of microRNAs to control cell death and differentiation. Cell Death and Differentiation, 20(10), 1370 - 1380. https://doi.org/10.1038/cdd.2013.92
Salmanidis, Marika ; Brumatti, Gabriela ; Narayan, Nisha ; Green, Benjamin D ; van den Bergen, Jocelyn A ; Sandow, Jarrod J ; Bert, Andrew G ; Silke, Natasha ; Sladic, Rosemary ; Puthalakath, Hamsa ; Rohrbeck, Leona ; Okamoto, Toru ; Bouillet, Phillipe ; Herold, Marco J ; Goodall, Gregory John ; Jabbour, Anissa ; Ekert, Paul G. / Hoxb8 regulates expression of microRNAs to control cell death and differentiation. In: Cell Death and Differentiation. 2013 ; Vol. 20, No. 10. pp. 1370 - 1380.
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title = "Hoxb8 regulates expression of microRNAs to control cell death and differentiation",
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.",
author = "Marika Salmanidis and Gabriela Brumatti and Nisha Narayan and Green, {Benjamin D} and {van den Bergen}, {Jocelyn A} and Sandow, {Jarrod J} and Bert, {Andrew G} and Natasha Silke and Rosemary Sladic and Hamsa Puthalakath and Leona Rohrbeck and Toru Okamoto and Phillipe Bouillet and Herold, {Marco J} and Goodall, {Gregory John} and Anissa Jabbour and Ekert, {Paul G}",
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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, A & Ekert, PG 2013, 'Hoxb8 regulates expression of microRNAs to control cell death and differentiation', Cell Death and Differentiation, vol. 20, no. 10, pp. 1370 - 1380. https://doi.org/10.1038/cdd.2013.92

Hoxb8 regulates expression of microRNAs to control cell death and differentiation. / Salmanidis, Marika; Brumatti, Gabriela; Narayan, Nisha; Green, Benjamin D; van den Bergen, Jocelyn A; Sandow, Jarrod J; Bert, Andrew G; Silke, Natasha; Sladic, Rosemary; Puthalakath, Hamsa; Rohrbeck, Leona; Okamoto, Toru; Bouillet, Phillipe; Herold, Marco J; Goodall, Gregory John; Jabbour, Anissa; Ekert, Paul G.

In: Cell Death and Differentiation, Vol. 20, No. 10, 2013, p. 1370 - 1380.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Hoxb8 regulates expression of microRNAs to control cell death and differentiation

AU - Salmanidis, Marika

AU - Brumatti, Gabriela

AU - Narayan, Nisha

AU - Green, Benjamin D

AU - van den Bergen, Jocelyn A

AU - Sandow, Jarrod J

AU - Bert, Andrew G

AU - Silke, Natasha

AU - Sladic, Rosemary

AU - Puthalakath, Hamsa

AU - Rohrbeck, Leona

AU - Okamoto, Toru

AU - Bouillet, Phillipe

AU - Herold, Marco J

AU - Goodall, Gregory John

AU - Jabbour, Anissa

AU - Ekert, Paul G

PY - 2013

Y1 - 2013

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AB - 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.

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DO - 10.1038/cdd.2013.92

M3 - Article

VL - 20

SP - 1370

EP - 1380

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

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Salmanidis M, Brumatti G, Narayan N, Green BD, van den Bergen JA, Sandow JJ et al. Hoxb8 regulates expression of microRNAs to control cell death and differentiation. Cell Death and Differentiation. 2013;20(10):1370 - 1380. https://doi.org/10.1038/cdd.2013.92