Poster Presentation 25th Lorne Cancer Conference 2013

HoxA9-mediated immortalisation of myeloid progenitors requires Bcl-2 (#161)

Gabriela Brumatti 1 , Marika Salmanidis 1 , Natasha Silke 1 , Chung H Kok 2 , Jarrod J Sandow 1 , Jolanda Visser 1 , Anissa M Jabbour 1 , Stefan Glaser 1 , Philippe Bouillet 1 , Richard J D'Andrea 2 , Paul G Ekert 1
  1. WEHI, Parkville, VIC, Australia
  2. Department of Hematology, Centre for Cancer Biology, Adelaide, Australia

Deregulated expression of some Hox genes is associated with development of myeloproliferative disorders and leukaemia. Over-expressed Hox genes are thought to contribute to leukaemiagenesis by blocking myeloid differentiation. To further investigate the molecular mechanisms by which HoxA9 contributes to immortalisation of haematopoietic cells, we generated primary growth factor dependent myeloid cells in which HoxA9 expression is regulated by administration of 4-hydroxy-tamoxifen (4-OHT).  Maintenance of HoxA9 over-expression is required for continued cell survival and proliferation, even in the presence of growth factors and independent of any effect on differentiation. Using this conditional system we show that HoxA9 conditionally immortalises and repressed apoptosis of myeloid progenitors by directly regulating the expression of members of the Bcl-2 family and the subunits of the cytokine receptor. Loss of Hoxa9 resulted in a substantial decrease in the anti-apoptotic protein Bcl-2 and of the cytokines receptor IL-3-receptor-alpha chain and IL-3/IL-5/GMCSF ß-common chain and increased expression of the pro-apoptotic Bcl-2 family member Bmf. Further, regulation of the Bcl-2 seems to be essential as cells from Bcl-2 deficient mice fail to be immortalised by HoxA9 and downregulation of Bcl-2 in Hoxa9-factor-dependent cells induced cell death. Thus, our data suggest that regulation of Bcl-2 proteins by HoxA9 not only influences the capacity of cells to survive and proliferate, but also to differentiate. Over-expression of HoxA9 thereby contributes to myeloid transformation by regulating proliferation, differentiation and the apoptotic machinery.