How mutant cells turn into aggressive cancers discovered

New York: Scientists have discovered how a gene mutation found in several human cancers - including leukaemia, gliomas and melanoma - promotes the growth of aggressive tumours, a finding that may help develop new treatment for the deadly diseases.

"We've found the mechanism through which this mutation leads to a scrambling of the genome. That's when you get really massive tumours," said Eros Lazzerini Denchi, associate professor at The Scripps Research Institute (TSRI) in US. The research also suggests a possible way to kill these kinds of tumours by targeting an important enzyme.

The researchers studied mutations in a gene that codes for the protein POT1. This protein normally forms a protective cap around the ends of chromosomes (called telomeres), stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations. POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these
cells leads to the activation of an enzyme, called ATR, that triggers programmed cell death.

Knowing this, scientists in recent years were surprised to find recurrent mutations affecting POT1 in several human cancers, including leukaemia and melanoma.
"Somehow those cells found a way to survive - and thrive. We thought that if we could understand how that happens, maybe we could find a way to kill those cells," said Lazzerini Denchi, who co-led the study with Agnel Sfeir of New York
University (NYU) School of Medicine.

Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in a gene called p53. "The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas," said Lazzerini Denchi. P53, a well-known tumour suppressor gene, is a cunning accomplice. When mutated, it overrides the protective cell
death response initiated by ATR.

Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. These mutant cells go on to proliferate and become aggressive tumours. The findings led the team to consider a new strategy for
killing these tumours.

Scientists know that all cells - even cancer cells - will die if they have no ATR. Since tumours with mutant POT1 already have low ATR levels, the researchers think a medicine that knocks out the remaining ATR could kill tumours without affecting healthy cells. The study was published in the journal Cell Reports.