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. In a new study published online in Nature Genetics, Lane et al tracked the genetic chain of events that links a chromosomal abnormality in Down syndrome to the cellular havoc that occurs in 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 the Division of Hematologic Neoplasia at Dana-Farber Cancer Institute. “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 chromosome 21, an addition that may involve the entire chromosome or a portion of it.
Study Details
To trace the link between Down syndrome and ALL—specifically, the most common form of the disease known as B-cell ALL—Dr. Lane and and colleagues acquired a strain of mice that carry an extra copy of 31 genes found on chromosome 21 in humans.
“[B-cell] ALL occurs when the body produces too many immature B cells,” Dr. 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-cell] ALL patients do.”
The researchers then scanned the mice’s B cells to ascertain their molecular signature. 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-cell ALL in people with Down syndrome, Dr. Lane’s team focused on the genes controlled by PRC2. Using two sets of B-cell 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.
The question then was, what gene or group of genes was stifling PRC2 in Down syndrome patients’ B cells? Using cells from the mice with an extra copy of 31 genes, the investigators systematically switched off each of those genes to see its effect on the cells. 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,” Dr. Lane remarked. “This provides the long-sought after molecular link between Down syndrome and the development of B-cell ALL.”
Possible Drug Targets
Although there are currently no drugs that target HMGN1, which could potentially short-circuit the leukemia process in people with Down syndrome, the researchers suggested that histone demethylase inhibitors, which switch on PRC2, could have an antileukemic effect in some of those people.
As other forms of B-cell ALL also have the same 100-gene signature as the one discovered for B-cell ALL associated with Down syndrome, drug agents that target PRC2 might be effective in those cancers as well, Dr. Lane added.
Dr. Lane and David Weinstock, MD, of Dana-Faber and the Broad Institute of Harvard and MIT, are the corresponding authors for the Nature Genetics article.
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.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
