Withdrawn 25th Lorne Cancer Conference 2013


Stephanie Grabow 1 2 , Alex RD Delbridge 1 2 3 , Gemma L Kelly 2 , Priscilla N Kelly 4 , Philippe Bouillet 2 , Andreas Strasser 2
  1. Cancer Therapeutics CRC, Melbourne, Victoria, Australia
  2. Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  3. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  4. Metabolism Branch, National Cancer Institute/NIH, Bethesda, Maryland, USA

Evasion of apoptotic cell death is critical for tumorigenesis and it is widely believed that expression of anti-apoptotic Bcl-2 family members at endogenous levels is essential to sustain survival of cells undergoing neoplastic transformation. Previous studies using gene-targeted mice have shown that Bcl-xL, but surprisingly not Bcl-2 is critical for Myc-induced pre-B/B lymphoma development. It remains, however, unclear whether Bcl-xL is the sole pro-survival Bcl-2 family member required for tumorigenesis induced by deregulated Myc expression. Mcl-1, another Bcl-2 pro-survival family member, is critical for cell survival during the early stages of B lymphopoiesis and is expressed at abnormally high levels in several types of human B cell lymphomas where it causes resistance to chemotherapeutic drugs. We therefore examined the role of Mcl-1 in pre-B/B lymphoma development in Eµ-myc transgenic mice, a model of human Burkitt’s lymphoma, in which Myc over-expression under control of the immunoglobulin heavy chain gene enhancer () causes abnormally increased accumulation of pre-leukaemic pro-B/pre-B cells, which after acquisition of additional oncogenic mutations progresses to a malignant state. Remarkably, our results show that loss of only one allele of mcl-1 is sufficient to diminish the pre-leukaemic expansion of B lymphoid cells and to substantially prolong lymphoma-free survival of Eµ-myc transgenic mice. We therefore conclude that Mcl-1 is a key player, alongside with Bcl-xL, in Eµ-myc driven B cell lymphoma development.