HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia

// Gabriela Brumatti 1,2 , Marika Salmanidis 1,2,4* , Chung H Kok 6 , Rebecca A Bilardi 1,2 , Jarrod J Sandow 1,2 , Natasha Silke 1,2 , Kylie Mason 1,5 , Jolanda Visser 1,7 , Anissa M Jabbour 1,2 , Stefan P Glaser 1,2 , Toru Okamoto 8 , Philippe Bouillet 1,2 , Richard J D’Andrea 6 , and Paul G Ekert 1,2,3,4 1 Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Australia 2 Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Australia 3 Murdoch Children’s Research Institute and Children’s Cancer Centre, Royal Children’s Hospital, Flemington Rd, Parkville, Australia 4 Department of Pediatrics, University of Melbourne, Parkville, Australia 5 Department of Medicine, University of Melbourne, Parkville, Australia 6 Department of Hematology and Centre for Cancer Biology, SA Pathology, Adelaide; Department of Hematology and Oncology, the Queen Elizabeth Hospital, Woodville, Australia; The Discipline of Medicine, University of Adelaide. 7 University Medical Center Groningen, Hanzeplein 1, Groningen, Netherland 8 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan * Present address: Centre for Cancer Biology, SA Pathology, Adelaide, Australia. Correspondence: Paul Ekert, email: // Keywords : HoxA9, Bcl-2, Leukemia, apoptosis Received : August 20, 2013 Accepted : September 13, 2013 Published : September 15, 2013 Abstract Deregulated expression of Hox genes such as HoxA9 is associated with development of myeloproliferative disorders and leukemia and indicates a poor prognosis. To investigate the molecular mechanisms by which HoxA9 promotes immortalization of hematopoietic cells, we generated growth factor dependent myeloid cells in which HoxA9 expression is regulated by administration of 4-hydroxy-tamoxifen. Maintenance of HoxA9 overexpression is required for continued cell survival and proliferation, even in the presence of growth factors. We show for the first time that maintenance of Bcl-2 expression is critical for HoxA9-dependent immortalization and influences the latency of HoxA9-dependent leukemia. Hematopoietic cells lacking Bcl-2 were not immortalized by HoxA9 in vitro . Furthermore, deletion of Bcl-2 delayed the onset and reduced the severity of HoxA9/Meis1 and MLL-AF9 leukemias. This is the first description of a molecular link between HoxA9 and the regulation of Bcl-2 family members in acute myeloid leukemia.