Evasion from apoptosis is
critical for the development and expansion of malignant tumours. This was first
shown for lymphomas that were elicited by deregulated expression of the cell
cycle regulator c-Myc, which is abnormally over-expressed in ~70% of human cancers.
Identifying the factors critical for the sustained growth of established
Myc-driven lymphomas remains an important objective. Our experiments using Eµ-myc lymphomas in which Mcl-1 could be deleted acutely by tamoxifen induced
Cre activation demonstrated that sustained tumour growth is dependent on the
expression of the Bcl-2 pro-survival protein Mcl-1. Remarkably, these lymphomas
can only tolerate heterozygous loss of mcl-1
if they acquire a mutation in the tumour suppressor p53. It has been proposed
that mutant p53 proteins can directly or indirectly control expression of genes
that are critical for tumour growth. We have translated our findings from mouse
studies into human Burkitt Lymphoma (BL), a malignancy that is similarly driven
by c-Myc overexpression, and found that the growth of these tumours is similarly
dependent on Mcl-1 or Mcl-1 in combination with Bcl-xL. Furthermore, mutations
in the human p53 gene are frequently detected in BL cells. Our results suggest
that the combined weak targeting of mcl-1
and mutant p53 may serve as an attractive therapeutic strategy for the
treatment of Myc-driven lymphomas.