Although it has long been known that individuals with Down syndrome have an increased risk of developing acute lymphoblastic leukemia (ALL) during childhood, the reason has not been known. A connection now appears to have been found.
In a study now online ahead of print in Nature Genetics (doi:10.1038/ng.2949), researchers from Dana-Farber Cancer Institute have identified the genetic chain of events that links a chromosomal abnormality in Down syndrome to the change that occurs in ALL. The team notes that the findings are relevant for not only people with Down syndrome but also for others who develop ALL.
"For 80 years, it has not been clear why children with Down syndrome face a sharply elevated risk of ALL, but advances in technology-which make it possible to study blood cells and leukemias that model Down syndrome in the laboratory-have enabled us to make that link," the study's lead author, Andrew Lane, MD, PhD, of the Division of Hematologic Neoplasia, said in a news release.
People with Down syndrome have an increased risk for a variety of health problems, including heart defects, respiratory and hearing difficulties, and thyroid conditions. Their risk for childhood ALL is 20 times that of the general population. Down syndrome occurs in people who have an extra copy of chromosome 21, either the entire chromosome or just part of it.
For the research, he and his colleagues used a strain of mice that carry an extra copy of 31 genes found on chromosome 21 in humans. "When we tested the mice's B cells in the laboratory, we found they were abnormal and grew uncontrollably-just as B cells from B-cell ALL patients do."
As described in the news release, the researchers then scanned the mice's B cells to ascertain their molecular signature, and the chief difference was that in the abnormal cells, the PRC2 proteins were not functioning. Somehow, the loss of PRC2 was spurring the B cells to divide and proliferate before they were fully mature, Lane said.
To confirm that a shutdown of PRC2 is critical to the formation of B-ALL in people with Down syndrome, Lane's team focused on the genes controlled by PRC2: Using two sets of B-ALL cell samples-one from patients with Down syndrome, the other from patients without the syndrome-they measured the activity of thousands of different genes, looking for differences. About 100 genes turned out to be much more active in the Down syndrome group, all of which were under control of PRC2.
"When PRC2 is silenced-as it is in the B cells of Down syndrome patients-those 100 genes respond with a burst of activity, driving cell growth and division," he said.
The question then was, what gene or group of genes was stifling PRC2 in the B cells of Down syndrome patients. Using cells from the mice with an extra copy of 31 genes, the investigators switched off each of the genes. When they turned off the gene HMGN1, the cells stopped growing and died.
"We concluded that the extra copy of HMGN1 is important for turning off PRC2, and that, in turn, increases the cell proliferation," Lane said. "This provides the long-sought after molecular link between Down syndrome and the development of B-cell ALL."
Although there are currently no drugs that target HMGN1, which could potentially interfere with the leukemia process in people with Down syndrome, the researchers suggest that drugs that switch on PRC2 could have an anti-leukemic effect in some of those people. Work is now under way to improve these histone demethylase inhibitors, so they can be tested in cell samples and animal models.
Funding for the research was provided by the Conquer Cancer Foundation; the Lauri Strauss Leukemia Foundation; the Leukemia & Lymphoma Society; the Alex Lemonade Stand Foundation; the U.S. Department of Defense; the Israel Science Foundation; the U.S. Israel Binational Foundation; the Stellato Fund; and the National Institutes of Health.