Researchers have linked a mutation causing Down syndrome-associated leukemias to developmental abnormalities in megakaryocytes.
Experiments showed that the leukemia-associated GATA1 mutant, GATA1s, interferes with the enzyme calpain 2, which acts as an initial trigger for a chain of reactions that determines the size and shape of megakaryocytes.
This interference hinders the normal process of cellular enlargement and platelet production.
“It’s like there’s a long pipeline and there’s a clog,” explained study author Adam N. Goldfarb, MD, of the University of Virginia School of Medicine in Charlottesville.
“We think it’s this pipeline that’s getting clogged in this disease and other diseases.”
Dr Goldfarb and his colleagues explained this discovery in Developmental Cell.
The researchers found that leukemia cells with the GATA1s mutation display a critical deficiency of calpain 2. And the enzyme’s absence leaves them stuck in an early stage of development, contributing to the development of Down syndrome-associated leukemias.
That could be the case in other forms of leukemia as well, Dr Goldfarb noted.
“These leukemias in Down syndrome aren’t that common,” he said, “but this finding has implications for other leukemias in that it lets us understand basic growth and development patterns.”
The team discovered that restoring calpain 2 expression in affected cells fixed the problem and allowed normal megakaryocyte development to resume.
As such, the researchers speculate that calpain deficiency could be a key defect in Down syndrome-associated leukemias, which provides a potential target for therapeutic development.
The findings might also help us find a way to mimic the natural process that allows a subset of Down syndrome-associated leukemias to disappear spontaneously.
