Down Syndrome and Leukemia: New Link Discovered

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

In a study posted online by Nature Genetics (2014; doi:10.1038/ng.2949), 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.

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"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 Cancer Institute in Boston, Massachusetts. "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.

Down 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 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.

Genetic samples from patients with B-ALL who did or did not have Down syndrome were used to further examine the role of PRC2, which is silenced in the B cells of patients with Down syndrome. Studies in mice found that the B cells stopped growing and died when the HMGN1 gene was turned off, indicating that the extra copy of HMGN1 is important for turning off PRC2. Switching on PRC2 could be anti-leukemic.

"This provides the long sought after molecular link between Down syndrome and the development of B cell ALL," Lane remarked.

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