Walter and Eliza Hall Institute
Results of preclinical research suggest the prosurvival protein MCL-1 is the BCL-2 family member most important for the growth and survival of MYC-driven lymphomas.
Investigators found that MYC-driven lymphoma growth in mice and human cell lines was significantly more dependent upon MCL-1 than BCL-XL.
And mutations in p53 could diminish but not counteract this dependency.
The team described this research is Genes & Development.
The work built on more than 3 decades of research into how MYC drives cancer development, according to study author Gemma Kelly, PhD, of the Walter and Eliza Hall Institute in Victoria, Australia.
“For many years, we have known that proteins from the BCL-2 protein family enhance cell survival and cooperate with MYC to accelerate the development of cancer,” she said. “Until now, it was not known which specific BCL-2 family protein was most important for the survival and growth of MYC-driven cancers.”
To investigate, Dr Kelly and her colleagues first generated mice in which they could delete Mcl-1 or Bcl-x in c-MYC-driven lymphoma cells.
The researchers found that homozygous loss of Bcl-x slightly impaired lymphoma growth. Four percent of Bcl-x-deleted mice had complete lymphoma regression. The rest experienced a modest delay in tumor expansion and slightly prolonged survival compared to controls (P=0.0367).
On the other hand, homozygous Mcl-1 deletion prompted complete lymphoma regression in 30% of mice, and it significantly improved overall survival compared to controls (P<0.0001). Even heterozygous Mcl-1 deletion substantially impaired lymphoma growth.
The investigators also conducted experiments on human Burkitt lymphoma cell lines. And they found evidence suggesting the survival and growth of Burkitt lymphoma cells is largely dependent on MCL-1. In fact, sustained growth and survival may not depend on BCL-XL at all.
Finally, the researchers investigated the role p53 mutations play in MCL-1 dependency. The results showed that mutations in p53 can reduce but not ablate lymphomas’ dependency on MCL-1.
These findings suggest MCL-1 could be an attractive therapeutic target for MYC-driven cancers, the investigators said, particularly because the loss of a single Mcl-1 allele is well-tolerated in healthy tissues.
“Anticancer agents that target the protein BCL-2, which is closely related to MCL-1, are already showing promise in clinical trials . . . ,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute.
“We are hopeful that inhibitors of MCL-1 will soon become available for clinical testing. We will be very interested in determining whether these compounds could be used to treat MYC-driven cancers.”
