New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
