Dana-Farber researchers uncover link between Down syndrome and leukemia

Although doctors have long known that people with Down syndrome have a heightened risk of developing acute lymphoblastic leukemia (ALL) during childhood, they haven't been able to explain why. Now, a team of Dana-Farber Cancer Institute investigators has uncovered a connection between the two conditions.

In a study posted online today by the journal Nature Genetics, the researchers track the genetic chain of events that links a chromosomal abnormality in Down syndrome to the cellular havoc that occurs in ALL. Their findings are relevant not only to people with Down syndrome but also to many others who develop ALL.

"For 80 years, it hasn't been clear why children with Down syndrome face a sharply elevated risk of ALL," said the study's lead author, Andrew Lane, MD, PhD, of Dana-Farber's Division of Hematologic Neoplasia. "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."

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.

The syndrome occurs in people who have an extra copy of a single chromosome, known as chromosome 21. The addition may involve the entire chromosome or a portion of it.

To trace the link between Down syndrome and ALL - specifically, the most common form of the disease known as B cell ALL, or B-ALL - Lane, who is also a medical oncologist in the Dana-Farber/Brigham and Women's Cancer Center Adult Stem Cell Transplantation Program, and his colleagues acquired a strain of mice that carry an extra copy of 31 genes found on chromosome 21 in humans.

"B-ALL occurs when the body produces too many immature B cells, which are a type of white blood cell that normally fights infections," Lane explained. "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-ALL patients do."

The researchers then scanned the mice's B cells to ascertain their "molecular signature" - the pattern of gene activity that distinguished them from normal B cells in mice. The chief difference was that in the abnormal cells, the group of proteins called PRC2 was not functioning. Somehow, the loss of PRC2 was spurring the B cells to divide and proliferate before they were fully mature.

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 between the two sets. About 100 genes turned out to be much more active in the Down syndrome group, and all of them 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.