Poster Presentation 25th Lorne Cancer Conference 2013

Noxa and Puma are the main drivers of chemotherapy related apoptosis in MLL-AF9 AML (#121)

Rebecca A Bilardi 1 2 , Suzanne Cory 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, Vic, Australia

Opposing factions of the Bcl-2 family of proteins regulate cell life and death. One pro-apoptotic faction, the BH3-only proteins, are activated in response to a variety of stresses, such as cytokine deprivation, DNA damage and oncogene expression. This work aims to determine the role of individual BH3-only proteins in the treatment of acute myeloid leukaemia (AML). Chromosomal rearrangements are a common feature of AML and fusions on the MLL gene such as MLL-AF9, are typical of this.  Our approach is to infect foetal liver haemopoietic stem cells from wild type mice and mice lacking expression of one or more BH3-only proteins with a retrovirus containing the MLL-AF9 fusion gene and then use these cells to reconstitute haemopoiesis in irradiated recipient mice.  The resulting tumours have been screened for expression of Bcl-2 family members and cultured in vitro to determine their responses to chemotherapeutics, alone and in combination with the BH3-mimetic ABT-737.  The BH3-only proteins Noxa and Puma, but not Bim, have been found to be essential for cell death following exposure tostandard chemotherapeutic drugs. Resistance to treatment can be reduced by the addition of a BH3-mimetic. This work suggests that combination therapy with BH3-mimetic drugs may prove efficacious in the clinical treatment of AML.