Poster Presentation 25th Lorne Cancer Conference 2013

Role of pro­‐survival BCL-2 family members in haematopoiesis and acute myeloid leukemia.  (#186)

Stefan P Glaser 1 , Zhen Xu 1 , Delphine Merino 1 , Bouillet Philippe 1 , Trounson Evelyn 1 , Wei Andrew 2 , Guthridge Mark 2 , Fairlie Walter Douglas 1 , Lee F Erinna 1 , Herold J Marco 1 , Bertolino Patrick 3 , Roberts W Andrew 1 , Huang CS David 1 , Kile T Ben 1 , Metcalf Don 1 , Alexander S Warren 1 , Strasser S 1
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
  3. Centenary Institute, The University of Sydney, Sydney, Australia

The programmed suicide of cells (apoptosis) is essential for normal development and tissue homeostasis. The discovery that impaired apoptosis can lead to cancer and that many anti-cancer treatments kill tumour cells by activating the intrinsic apoptotic pathway has led to intense interest in uncovering effective ways of harnessing apoptotic pathways to develop new therapeutic options. The development of drugs that mimic BH3-only protein action by binding and inhibiting pro-survival BCL-2 family members has provided the opportunity for targeted therapy by triggering the intrinsic apoptosis pathway. ABT-263 is a recently developed BH3 mimetic currently in clinical trial, which potently inactivates BCL-2, BCL-XL and BCL-W but not MCL-1 or BCL2A1. The specificity of ABT-263 and the closely related molecule ABT-737 raises the possibility of targeting the pro-survival family members most critical for survival of a particular cancer, thereby reducing cytotoxicity to normal cells. It is therefore important to (i) examine which pro-survival BCL-2 family members are essential in a particular type of cancer to pinpoint the relevant ones that should be targeted and (ii) examine the requirements of pro-survival BCL-2 family members in normal cells and tissues to predict the toxicity induced by their therapeutic inhibition. We are using conditional knock-out mouse models and retroviral transduction of oncogenic proteins to investigate the role of pro-survival BCL-2 family proteins in haematopoiesis and acute myeloid leukemia.